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The objective of this study was to investigate the prognostic significance of the frequency of primary cilia (PC) and β-catenin expression in 218 patients (pts) with non-small cell lung cancer (NSCLC), including 125 pts with adenocarcinoma and 93 pts with squamous cell carcinoma. In the whole group of 218 pts with NSCLC, overall survival (OS) was significantly inferior among pts with present PC than without PC (p=0.024) and with higher cytoplasmic β-catenin expression (25-75%) than with lower cytoplasmic β-catenin expression (<25%) (p=0.008). In the univariate Cox proportional hazard model, the hazard ratio was 1.653 in pts with present PC (p=0.026) and 1.851 in pts with higher cytoplasmic β-catenin (25-75%) (p=0.009). Multivariate testing of the whole group of 218 pts with NSCLC showed that the presence of PC was associated with a worse prognosis (p=0.018). In the subgroup of 125 pts with adenocarcinoma, OS was significantly improved in pts with higher membranous β-catenin expression (≥50%) than in pts with lower expression (<50%) (p=0.0300) and OS was significantly inferior in pts with higher cytoplasmic β-catenin expression (25-75%) than in pts with lower expression (<25%) (p=0.0004). Multivariate testing of the subgroup of pts with adenocarcinoma showed that cytoplasmic β-catenin (p<0.001) and pleural invasion (p=0.017) were associated with worse prognosis. The present results indicate a negative prognostic significance of PC and cytoplasmic β-catenin expression in NSCLC and a negative prognostic significance of cytoplasmic β-catenin expression in adenocarcinoma.

Many lines of evidence suggest that circular RNAs (circRNAs) are closely associated with the occurrence and progression of colon cancer. The objective of this study was to investigate the regulatory effects and mechanisms of circ_0075829 on ferroptosis and immune escape in colon cancer. We utilized colon cancer cell lines and a xenograft mouse model to analyze the function of circ_0075829 in vitro and in vivo. The gene expression level was assessed by qRT-PCR and western blotting. Cell proliferation was evaluated using the CCK-8 assay. The targeting relationships between circ_0075829, miR-330-5p, and TCF4 were analyzed through a dual-luciferase reporter experiment and RNA pull-down experiment. Cytokine levels were measured using the ELISA assay. Fe2+, MDA, and SOD levels were tested using appropriate kits, and the ROS level was detected by immunofluorescence. Knockdown of circ_0075829 resulted in increased levels of Fe2+, ROS, and MDA and decreased levels of GPX4 and xCT proteins in cells. Furthermore, silencing of circ_0075829 increased the cell proliferation rates of CD8+T cells co-cultured with colon cells. Moreover, it also enhanced IFN-γ, IL-2, and TNF-α concentration in the supernatants of the co-culturing system and reduced PD-L1 protein expression levels. Subsequently, silencing of circ_0075829 induced ferroptosis and inhibited immune escape in vivo. Meaningfully, we certified that circ_0075829 functions as a sponge for miR-330-5p, leading to the upregulation of TCF4 expression. TCF4 was identified as a downstream target of miR-330-5p. Additionally, co-transfection with anti-miR-330-5p or TCF4 overexpression plasmid reversed the effects observed following the knockout of circ_0075829. Collectively, our research indicates that the circ_0075829 plays a significant role in regulating ferroptosis and immune escape in colon cancer by sponging miR-330-5p to modulate TCF4 expression.

DNA methylation is recognized as an early event in cancer initiation and progression. This review aimed to compare the methylation status of promoter regions in selected genes across different histological subtypes of non-small cell lung cancer (NSCLC), including adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and the rare but highly aggressive large-cell neuroendocrine carcinoma (LCNEC). A comprehensive literature search was conducted in the PubMed database until August 17, 2024, using standardized keywords to identify reports on promoter methylation in NSCLC. Seventy-five studies were reviewed, focusing on the promoter methylation of key genes, such as APC, BRCA1, CDH1, CDH13, DAPK1, DLEC1, FHIT, GSTP1, hMLH1, MGMT, CDKN2A, RARβ, RASSF1, RUNX3, and TIMP3. These studies explored diagnostic, prognostic, epidemiological, and therapeutic aspects across NSCLC subtypes. Additionally, mutational profiles of TP53, RB1, KEAP1, and STK11 and expression patterns of ASCL1, DLL3, and NOTCH were analyzed. The findings suggest that LCNEC may serve as a biological bridge between non-small cell and small-cell lung carcinoma. Our analysis highlights that the methylation status of selected genes could enhance diagnosis, prognosis, and personalized treatment strategies in patients with NSCLC, particularly those with LCNEC.

Pediatric central nervous system (CNS) tumors represent 20-25% of childhood malignancies, with 35-40 new cases annually in Slovakia. Despite treatment advances, high mortality and poor quality of life in a lot of cases persist. This study assesses the clinical features, treatment modalities, and survival rates of pediatric CNS tumor patients in the single largest center in Slovakia. A retrospective analysis was conducted on pediatric CNS tumors from January 1, 2000, to December 31, 2020, at the Department of Pediatric Oncology and Hematology at the National Institute of Children's Diseases in Bratislava, Slovakia. Among 397 patients (242 males, 155 females), the most common histological types were astrocytomas (42.8%), followed by embryonal tumors (18.4%), brain stem tumors (10.3%), and ependymal tumors (8.1%). Tumor locations were supratentorial (48.1%), infratentorial (46.9%), and spinal (4.3%). Surgical interventions included radical excision (30.2%), subtotal/partial excision (41.8%), and biopsy (9.3%). Treatment modalities varied, with 31.2% receiving combined surgery, chemotherapy, and radiotherapy; 27.5% surgery alone; 9.6% surgery with radiotherapy; 7.8% chemotherapy only; and 6.3% having no treatment. By 2020, 74.3% of patients were alive, with a 25.7% mortality rate. This study outlines the characteristics of pediatric CNS tumors in Bratislava, highlighting the need for multidisciplinary national and international collaboration to advance diagnosis and treatment. Our data align with global findings from other centers.

Esophageal squamous cell carcinoma (ESCC) has high mortality. The role and regulatory mechanism of hsa_circ_0021727 (circ_0021727) in ESCC remain largely unknown. This study focused on the undiscovered impact of circ_0021727 on cell cycle progression, apoptosis, and angiogenesis of ESCC. We found that circ_0021727 levels were significantly upregulated in ESCC cells. TUNEL, flow cytometry, and tubule formation assay indicated that knockdown of circ_0021727 in ESCC induced cell arrest at the G0/G1 phase, promoted apoptosis, and inhibited angiogenesis, whereas overexpression of circ_0021727 produced the opposite effect. Gastrulation brain homeobox 2 (GBX2) GBX2 was a downstream target gene of circ_0021727, and overexpression of GBX2 reversed the effect of circ_0021727 knockdown in ESCC progression. The results of the RIP and RNA pull-down showed that circ_0021727 and GBX2 mRNA bound with eukaryotic translation initiation factor 4A3 (EIF4A3). Overexpression of circ_0021727 promoted GBX2 mRNA stability by binding with EIF4A3. In a tumor xenograft model, the knockdown of circ_0021727 inhibited tumor growth, which was reversed by further overexpression of GBX2. In conclusion, circ_0021727 increased GBX2 mRNA stability by recruiting EIF4A3, which promoted cell cycle progression and angiogenesis in ESCC.

MTHFD2 is highly overexpressed in breast cancer tissues, indicating that it might be used as a target in breast cancer treatment. This study aims to determine the role of MTHFD2 in breast cancer cell proliferation and the molecular pathways involved. In order to investigate MTHFD2 gene expression and its downstream pathways in breast cancer, we started our inquiry with a bioinformatics analysis. We then engineered breast cancer cell lines with either silenced or overexpressed MTHFD2 to study its effects on the cell cycle, proliferation, and the m6A methylation status of the gene IFRD1, predicted as a downstream target. Overexpression of MTHFD2 enhanced cellular proliferation, increased the proportion of EdU-positive cells, and accelerated progression into the S+G2/M phase. In contrast, MTHFD2 knockdown led to opposite effects. MTHFD2 and IFRD1 expression levels showed a strong positive association. Increased MTHFD2 activity boosted HDAC3 and mTOR phosphorylation, activating p70 S6K and 4EBP1-key regulators of cell proliferation. Moreover, overexpression of MTHFD2 was associated with reduced p53 acetylation and total protein levels. Silencing MTHFD2 decreased m6A methylation of IFRD1 RNA, whereas its overexpression increased methylation. Notably, IFRD1 siRNA transfection reversed the proliferative effects induced by MTHFD2 overexpression. Furthermore, MTHFD2 knockdown enhanced the sensitivity of breast cancer cells to several chemotherapeutic agents. In conclusion, MTHFD2 influences breast cancer cell proliferation by modulating the m6A methylation of IFRD1 RNA, which regulates the HDAC3/p53/mTOR pathway. These findings suggest that MTHFD2 inhibitors may synergistically enhance the efficacy of existing chemotherapies.

Regarding flotillin knockdown, drug resistance is reversed in colorectal cancer (CRC) cell lines; this is associated with the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway, as our previous experimental results indicated. However, the exact mechanism underlying this pathway remains unclear. PI3K inhibitor and activator were added separately to clarify the role of the PI3K pathway in reversing drug resistance. The results showed decreased resistance after inhibiting PI3K activity. Furthermore, the reduced resistance due to flotillin knockdown was restored after adding the PI3K activator. Additional results showed no changes in PI3K molecules. However, p-AKT expression was downregulated. Further results suggested that the phosphatidylinositol (3,4,5)-trisphosphate/phosphatidylinositol 4,5-bisphosphate (PIP3/PIP2) ratio was downregulated, whereas the phosphatase and tensin homolog (PTEN) expression was upregulated. In addition, we also found that P-gp activity inhibition resulted in increased adriamycin accumulation and reversal of resistance, and flotillin knockdown was accompanied by a downregulation of P-gp expression in CRC cells. In conclusion, our study demonstrated that flotillin knockdown could reverse drug resistance in CRC cells by downregulating the PTEN/PI3K/AKT pathway and P-gp.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast malignancy. Although some patients benefit from immune checkpoint therapy, current treatment methods rely mainly on chemotherapy. It is imperative to develop predictors of efficacy and identify individuals who will be sensitive to particular treatment regimens. This study analyzed peripheral interferons and immune cell subsets in TNBC patients receiving pre-operative neoadjuvant therapy. The effects of interferon-induced helicase 1 (IFIH1) on the biological characteristics of apoptosis and PD-L1 expression of cancer cells and its potential mechanism were investigated using bioinformatics analysis, clinical specimens, and in vitro study. We found that serum interferon-γ and interferon-α2 levels were significantly higher in TNBC patients with pathologic complete response (pCR). The expression of IFIH1 is markedly upregulated in various tumors, including breast cancer. Immunohistochemical results revealed that IFIH1 was specifically located in the cytoplasm of cancer cells. Gene set enrichment analysis showed that genes co-expressed with IFIH1 were involved in tumor immune-related pathways and apoptosis. Knockdown of IFIH1 in MDA-MB-231 and BT-549 cells resulted in significantly increased cell proliferation and colony formation. Regarding apoptosis-related pathway proteins, there was a significant decrease in levels of phosphorylated TANK-binding kinase 1 (TBK1) and phosphorylated interferon regulatory factor 3 (IRF3). In addition, the expression of PD-L1 was significantly downregulated. Furthermore, we demonstrated the existence of binding sites between IRF3 and PD-L1 promotors. Our data indicate that cancer cell IFIH1 promotes apoptosis and PD-L1 expression, suggesting its potential as a predictive marker of efficacy and therapeutic target in TNBC.

This study focuses on exploring the role of Six2 in the progression of hepatocellular carcinoma (HCC) and its resistance to the chemotherapy drug 5-fluorouracil (5-FU). Using Hep3B and Huh7 cell lines, we analyzed how Six2 affects various cellular functions, including viability, proliferation, apoptosis, and invasion. Our research also delved into Six2's regulatory impact on DNMT1 levels, E-cadherin expression, and the methylation of the E-cadherin promoter, all of which are crucial for 5-FU resistance in HCC cells. Additionally, we examined the effects of Six2 knockdown on the PI3K/AKT/mTOR signaling pathway. Our findings indicate that overexpression of Six2 enhances cell viability and proliferation, encourages invasive behavior, increases methylation at the E-cadherin promoter, and reduces apoptosis. These changes correspond with increased levels of DNMT1 and decreased levels of E-cadherin, culminating in heightened resistance to 5-FU. Conversely, knocking down Six2 increases the sensitivity of HCC cells to 5-FU and reduces activation of the PI3K/AKT/mTOR pathway. These results suggest that Six2 plays a significant role in promoting HCC proliferation, invasion, and chemotherapy resistance, particularly through mechanisms involving DNMT1 and the PI3K/AKT/mTOR pathway, highlighting its potential as a target for HCC treatment.

Prostate cancer (PCa) is the most frequently diagnosed malignant tumor in males, and there are currently few effective therapeutic targets following hormone therapy resistance. Subunits of eukaryotic initiation factor 3 (eIF3) have been implicated in the progression of various cancers. This study aims to investigate the biological functions of the eIF3m subunit in PCa and assess its potential as a novel therapeutic target for treatment. We utilized open-access datasets and patient tissues to analyze the expression and prognostic value of eIF3m in PCa. To explore the role of eIF3m in PCa growth, we established eIF3m knockdown models in PC3 and 22Rv1 cells for both in vitro and in vivo studies. Gene set enrichment analysis (GSEA) was utilized to identify signaling pathways regulated by eIF3m in PCa. Additionally, western blotting and immunochemistry were used to confirm the regulation of c-Myc signaling by eIF3m in PCa. Our results indicated that eIF3m expression was elevated in PCa tissues, with higher levels correlating with an increased risk of biochemical recurrence following radical prostatectomy. Both in vitro and in vivo experiments demonstrated that inhibiting eIF3m significantly impeded the growth of PCa cells. GSEA and immunochemistry further revealed that high eIF3m expression contributed to the activation of c-Myc signaling in PCa patients. Notably, the downregulation of eIF3m resulted in a significant decrease in the expression of c-Myc mRNA and protein in PCa cells. Overall, our findings suggest that eIF3m inhibition significantly suppressed PCa cell growth and c-Myc signaling, indicating that eIF3m is a promising therapeutic target for PCa patients.