Cancer Genomics & Proteomics最新文献

Background/aim: Hepatocellular carcinoma (HCC) accounts for ~90% of primary liver cancer, which ranks as the third-leading cause of global cancer mortality. Emerging evidence establishes cancer stem cells (CSCs) as central regulators of HCC progression, metastasis, and therapeutic resistance, with stemness-related pathways like Wnt/β-catenin signaling critically maintaining CSC self-renewal. In this study, we aimed to investigate the role of Peptidyl-prolyl isomerase-like 1 (PPIL1) in HCC progression and CSC self-renewal.

Materials and methods: PPIL1 expression patterns were systematically analyzed using The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) data and validated in primary HCC specimens via qRT-PCR and western blot. PPIL1 was knocked down in HCC cell lines using shRNAs, and cell viability, migration, and sphere formation were assessed in vitro. Xenograft mouse models were established to evaluate the effects of PPIL1 on tumor growth kinetics and liver CSC-related properties. Transcriptome analysis was performed to identify downstream targets and signaling pathways affected by PPIL1 knockdown.

Results: Our analysis revealed significantly elevated PPIL1 expression in HCC tumors and liver CSCs, with its expression level positively correlating with tumor stage and histological grade. PPIL1 knockdown effectively suppressed HCC cell proliferation, migration, and in vivo tumor growth. The essential role of PPIL1 in liver CSC maintenance was demonstrated by impaired sphere-forming capacity and diminished tumor initiation potential. Mechanistic studies identified PPIL1 as a regulator of Wnt/β-catenin signaling through transcriptional up-regulation of dishevelled associated activator of morphogenesis 2 (DAAM2).

Conclusion: Our findings suggest PPIL1 to be a crucial regulator of HCC progression and liver CSC maintenance via DAAM2-mediated Wnt/β-catenin activation. This positions PPIL1 as a promising molecular target for HCC therapy, with particular relevance for addressing CSC-driven therapeutic resistance.

In order to identify new treatment modalities and targets for the treatment of bladder cancer (BLC), we have searched the literature (PubMed) for circular RNAs (circRNAs) that mediate efficacy in preclinical BLC-related in vivo systems. Pathogenesis-affecting circRNAs can be up-regulated or down-regulated depending on their function as oncogenes or tumor suppressors. We have grouped the identified circRNAs according to functional aspects or protein categories, such as involvement in drug resistance, transmembrane proteins, secreted proteins, mediators of signaling, enzymes with pathogenic potential, transcription factors, as well as circRNAs involved in microRNA (miR) processing and epigenetic modifications. The identified up-regulated targets can be modulated with small molecules or antibody-based drugs depending on their druggability. Down-regulated circRNAs can potentially be reconstituted by replacement therapy, whereas up-regulated circRNAs can be inhibited by nucleic acid (NA)-based inhibitors. The validity of the approach of exploring circRNAs and their corresponding targets for therapeutic intervention was underlined by the identification of circRNAs that up-regulate fibroblast growth factor receptors, which can be inhibited by erdafitinib, an approved agent for the treatment of bladder cancer.

Background/aim: Pioglitazone (PIO), a peroxisome proliferator-activated receptor gamma agonist, is typically used to treat type 2 diabetes mellitus. In addition to its metabolic effects, PIO exhibits various biological activities, including potential anticancer effects. However, its efficacy and mechanistic relevance in the development and progression of cancer, including urothelial carcinoma, remain unclear. Herein, we investigated the functional impact of PIO on urothelial tumorigenesis.

Materials and methods: An in vitro urothelial neoplastic transformation model was established by inducing SV-HUC-1 cells with a chemical carcinogen 3-methylcholanthrene. This model was used to investigate the effects of PIO on neoplastic/malignant transformation.

Results: PIO significantly inhibited the neoplastic/malignant transformation of SV-HUC-1 cells. Moreover, PIO treatment up-regulated tumor suppressors, including p53 and phosphatase and tensin homolog (PTEN), as well as the epithelial marker E-cadherin, while down-regulating the mesenchymal marker N-cadherin and the oncogenic factor nuclear factor kappa B (NF-κB), as confirmed by protein and mRNA expression analyses.

Conclusion: PIO has a chemopreventive effect on urothelial tumorigenesis, supporting its potential use as a preferred anti-diabetic agent for patients with a risk or history of urothelial carcinoma.

Background/aim: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, with a mean incidence of 5.1 cases per million people per year. At least 40% of uveal melanoma patients ultimately develop distant metastasis. But unlike cutaneous melanoma, targeted therapies and immune checkpoint blockers have shown limited effects. Investigating the metastasis-related pathogenesis mechanisms of uveal melanoma could facilitate the development of potential therapies.

Materials and methods: For this purpose, we integrated microarray gene expression data (GSE22138) and an independent TCGA dataset to identify derlin-1 (DERL1) as our candidate gene. In vitro cellular assays were conducted to examine DERL1's role in the pathogenesis of uveal melanoma.

Results: DERL1 up-regulation was identified in metastatic UM based on the microarray dataset, which was consistent with the TCGA dataset. However, the detailed mechanism has not yet been investigated. Therefore, we manipulated DERL1 expression with siRNA in a uveal melanoma cell line. After confirming the successful knockdown of DERL1, in vitro oncogenicity and chemosensitivity were assessed. Knockdown of DERL1 repressed cell proliferation and impaired cell migration and invasion. Furthermore, uveal melanoma cells with DERL1 knockdown had increased chemosensitivity to cisplatin and a decreased cancer stem cell potential determined by examining the intensity of CD133 and CD271.

Conclusion: By analyzing GEO and TCGA datasets combined with in vitro cellular assays, DERL1 was found to be associated with metastasis in uveal melanoma and to be a possible target for further treatment.

Background/aim: Glioblastoma multiforme (GBM) is a highly aggressive, treatment-resistant brain tumor with a dismal prognosis, and identifying key molecules involved in its therapeutic resistance is essential to improve patient outcomes. This study was undertaken to identify hub genes associated with the radioresistance and temozolomide (TMZ) resistance of GBM using bioinformatics analysis.

Materials and methods: RNA-seq and microarray datasets from the GEO database were analyzed to identify differentially expressed genes (DEGs). GO and KEGG pathway enrichment analyses were performed using Enrichr. A protein-protein interaction (PPI) network was constructed using STRING and visualized with Cytoscape, and hub genes were identified by MCODE analysis. Expression and survival analyses were conducted on TCGA and GTEx datasets using GEPIA2.

Results: Twenty-four DEGs were considered linked to radioresistance and 122 to TMZ resistance. Functional enrichment and PPI network analyses highlighted key therapeutic resistance pathways, including cytokine-mediated signaling and inflammatory response pathways. Notably, CXCL8, IL1A, and IL1B were identified as key hub genes significantly enriched in these pathways. Expression analysis confirmed their up-regulation in GBM, and survival analysis indicated their association with prognosis.

Conclusion: This study identifies CXCL8, IL1A, and IL1B as potential therapeutic targets for overcoming the resistance of GBM to radiotherapy and chemotherapy. In addition, these genes might serve as prognostic biomarkers and key regulators of GBM malignancy. Future studies are warranted to explore their functional roles in vivo and assess their potential use as therapeutic intervention targets.

Background/aim: Typically expressed on T-cells and NK cells, FASLG induces apoptosis in target cells upon binding Fas. However, assessing potential FASLG expression in tumor cells with convenient genomics approaches has been challenging.

Materials and methods: This study applied a novel assessment of FASLG copy numbers (CNs) and gene expression levels, applicable to bulk exome and RNAseq files.

Results: Analyses indicated high FASLG CN associated with worse survival outcomes. Interestingly, higher FASLG gene expression was found to be associated with better survival outcomes, which led to a determination of whether this result was due to FASLG expression from tumor-infiltrating lymphocytes (TILs) instead of cancer cells demonstrating the higher CNs. In fact, T-cell markers CD4 and CD8A highly correlated with FASLG expression, consistent with the hypothesis that the high FASLG expression was associated with the TILs. Subsequent analyses confirmed that CN increases led to increased gene expression in the genomic region of the FASLG gene, particularly with an assessment of the expression of the neighboring PRRC2C gene. In sum, FASLG CN assessments, even independently of a corresponding gene expression correlation, may provide important characterizations of tumor cells.

Conclusion: This study indicates that FASLG CN increases could represent a mechanism of tumor escape from TILs and a prognostic indicator; and tumor FASLG may be a suitable drug target for reducing tumor evasion of T-cells.

Background/aim: Lung cancer is the most prevalent type of cancer and the leading cause of cancer-related mortality worldwide. Understanding the detailed mechanisms of lung carcinogenesis can improve the survival rates of patients with lung cancer. Long noncoding RNAs (lncRNAs) are large (>200 nucleotides) noncoding RNAs that play a key role in various types of human cancer by regulating the proliferation, apoptosis, and metastasis of cancer cells. LOC100506691 is an oncogene that promotes the growth and metastasis of cancer cells. However, its biological role in lung cancer remains unknown.

Materials and methods: The expression levels and clinical significance of LOC100506691 in lung cancer were analyzed using public databases. The biological function of LOC100506691 was investigated in lung cancer cell lines following siRNA-mediated knockdown, with assessments of cell proliferation, colony formation, motility, apoptosis, and cell cycle progression. Potential signaling pathways affected by LOC100506691 knockdown were examined through western blotting and pathway enrichment analysis.

Results: According to public databases, the expression of LOC100506691 is significantly higher in lung cancer cells than in adjacent normal tissues. These high expression levels of LOC100506691 are strongly associated with poor survival outcomes in patients with lung cancer. Knockdown of LOC100506691 significantly suppresses the proliferation, colony formation ability, and metastasis of lung cancer cells. In lung cancer cells, LOC100506691 knockdown impairs the cell cycle progression and induces apoptosis by modulating the PI3K/AKT signaling pathway.

Conclusion: Our findings indicate that LOC100506691 is a novel lncRNA that promotes the growth and metastasis of lung cancer cells and therefore provide valuable insights that can aid in the development of lung cancer therapy.

Background/aim: Acute lymphoblastic leukemia (ALL) is the most common pediatric hematologic malignancy, particularly affecting children aged 2~5 years. Tissue inhibitor of metalloproteinase-2 (TIMP-2), a key regulator of MMP-2 activity, has been implicated in several cancers, yet its genetic role in childhood ALL remains unexplored.

Materials and methods: This study investigated four TIMP-2 polymorphic genotypes, rs8179090, rs4789936, rs2009196, and rs7342880, in 266 Taiwanese children with ALL and 266 matched controls using polymerase chain reaction-restriction fragment length polymorphism methodology.

Results: TIMP-2 rs8179090 exhibited a significant association with ALL risk. Individuals with the CC genotype had a markedly increased risk [odds ratio (OR)=4.01, 95% confidence interval (CI)=1.46-11.04, p=0.0076], particularly under a recessive model (OR=3.79, 95%CI=1.39-10.36, p=0.0105). The C allele frequency was also elevated in cases (20.7%) versus controls (14.5%) (p=0.0100). Stratified analysis showed stronger risk association in children aged ≤3.5 years (CC genotype: OR=5.06, p=0.0084) and in boys (CC genotype: OR=5.53, p=0.0046). Moreover, CG+CC genotypes were associated with higher clinical risk classification (OR=2.25, p=0.0031) and shorter survival (<5 years) (OR=3.68, p=0.0003), though no correlation was found with immunophenotypic subtypes. No significant associations were identified for rs4789936, rs2009196, or rs7342880.

Conclusion: TIMP-2 rs8179090, particularly the CC genotype, may serve as a novel biomarker for childhood ALL susceptibility and prognosis, especially in younger and male patients. Genotyping of this polymorphism could support early risk assessment and personalized clinical management in childhood ALL.

Background/aim: Cytarabine is the main chemotherapy agent used to treat acute myeloid leukemia (AML), but drug resistance remains a major challenge. Imbalances in cytokine secretion are known to play a role in the survival and proliferation of AML blast cells. While numerous studies have investigated cytokine secretion in AML, the precise role of cytokines in the pathogenesis of AML remains unclear. This study aimed to compare cytokine-related gene expression in parental and resistant HL60 cells and assess their prognostic relevance in AML.

Materials and methods: This study compared gene expression profiles of parental HL60 and R-HL60 cells by analyzing gene expression arrays. Further, the correlation between the differential expression genes (DEGs) and overall survival in patients with AML was obtained from the Cancer Genome Atlas (TCGA) database, and the expression of genes was validated by quantitative PCR (QPCR).

Results: Our results showed that twenty-six genes involved in cytokine regulation were significantly different between HL60 and R-HL60 cells. The DEGs associated with cytokine production between parental HL60 and R-HL60 was subjected to a functional enrichment analysis by ShinyGO. The expression of BCL3, OAS3, RELB, AIM2, NFKB2, CLEC9A, and OAS2 involved in the regulation of cytokine production was associated with survival probability of AML patient in the TCGA database. Among them, the expression of BCL3, OAS3, RELB, AIM2, and NFKB2 genes in R-HL60 cells was higher than that in HL-60 cells.

Conclusion: This study identified key genes involved in cytokine dysregulation in cytarabine-resistant HL60 cells, providing potential targets for overcoming drug resistance in AML. These findings offer new avenues for the development of more effective therapies for relapsed or refractory AML patients.

Background/aim: Cell lines serve as valuable in vitro models to study altered cellular signaling pathways, to identify mutations in key oncogenic genes, and to test potential antitumor drugs. The Jurkat cell line, for example, has provided important information about various signaling pathways in lymphoblastic leukemia, establishing most of what is currently known about T-cell receptor (TCR) signaling. However, many aspects of the genome modification of this cell line have not yet been analyzed. To identify genes of potential biological and clinical relevance in acute T-lymphoblastic leukemia (T-ALL), we performed an array comparative genomic hybridization (aCGH) approach on the widely used Jurkat cell line and examined the association of the detected copy number alterations (CNAs) with cancer hallmarks and T-ALL pathogenesis.

Materials and methods: Cells were harvested by using trypsin/EDTA from culture flasks to extract genomic DNA. aCGH experiments were performed on an Agilent microarray platform using the SurePrint G3 Cancer CGH + SNP Microarray 4×180 K. Functional enrichment analysis of all CNAs was performed with the R package g:Profiler2. The association of these alterations with key cancer hallmarks was analyzed using the Cancer Hallmarks web-tool.

Results: Our analysis revealed several novel CNAs, including losses at 5p15.2, 6q27, 10q22.2, 14q11.2, 18q11.2-q12.1, and Xp22.33, as well as gains at 2p11.2, 7p21.2, 7q21.2 and 18p11.32. Genes within these regions were associated with important oncogenic pathways, including 'sustained proliferative signaling', 'tumor suppressor evasion', and 'angiogenesis promotion'.

Conclusion: These findings suggest that Jurkat cells may serve as a valuable model for identifying new targets for cancer research. Further studies are required to confirm the phenotypic implications of these variants, which may open new avenues for exploring the functional impact of these alterations and their potential role in the development of therapies.