BackgroundPapillary thyroid carcinoma (PTC), the most common thyroid malignancy, shows marked clinical heterogeneity despite generally favorable outcomes. Lysosome-dependent cell death (LDCD), a form of programmed death triggered by lysosomal membrane permeabilization, has emerged as a potential cancer therapy target, but its role in PTC remains unclear.MethodsTranscriptomic data from public cohorts were analyzed to identify LDCD-related genes (LDCDRG) associated with PTC prognosis. Cox analysis and LASSO regression analyses were performed to construct a prognostic model. Immune landscape, drug sensitivity, and single-cell expression profiles were examined. Functional experiments were conducted in vitro to verify the biological effects of the key gene LMTK3 on PTC cell proliferation, viability, and invasion.ResultsNineteen LDCDRG were differentially expressed between normal and tumor tissues, defining three molecular subtypes with distinct immune and prognostic profiles. A six-LDCDRG signature (LMTK3, MCM5, NXF1, TUBB4B, LIMCH1 and APH1B) effectively stratified patients into high- and low-risk groups with significantly different survival outcomes and acceptable predictive performance. High-risk patients showed reduced immune infiltration and lower predicted immunotherapy-related immune activity. LMTK3, the highest-risk gene, was highly expressed in PTC cells, and its knockdown suppressed proliferation and invasion in vitro.ConclusionsThe established six-LDCDRG signature provides an exploratory tool for risk stratification and survival prediction, while LMTK3 emerges as potential target worthy of further investigation. These findings deepen our understanding of lysosome-dependent cell death in thyroid carcinogenesis and may provide insights into the development of personalized management strategies and novel treatment approaches for high-risk PTC patients.

BackgroundRNF216 belongs to the E3 ubiquitin ligase family and plays a role in the development of various diseases. However, its systematic role in pan-cancer development has not been systematically explored.MethodsPublicly available data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and the Human Protein Atlas (HPA) were utilized. The analysis was conducted using R software and online platforms such as STRING, TISIDB, and TISCH to evaluate the role of RNF216. CCK-8 and other experiments have confirmed the function of RNF216 in liver hepatocellular carcinoma (LIHC).ResultsRNF216 was significantly elevated in most tumor tissues relative to adjacent normal tissues; meanwhile, the mutation rate of RNF216 in LIHC tissues was also significantly elevated relative to normal tissues. The expression levels of RNF216 vary in tumor mutational burden (TMB) and microsatellite instability (MSI) across different tumors. It demonstrated significant diagnostic and prognostic value and was associated with clinicopathologic features in multiple cancers, especially in LIHC. The protein-protein interaction (PPI) network and GSCALite suggested that RNF216 and its co-expressed genes may promote tumor growth by regulating mitosis, cell death, and DNA damage. Gene Set Enrichment Analysis (GSEA) further revealed a positive correlation between RNF216 and cell cycle regulation pathways. RNF216 is significantly related to immune cell infiltration and expressed in various types of immune cells. Knockout of RNF216 mediated by siRNA inhibits cell proliferation and reduces the migration and invasion capability of HepG2 and Hep3B cells.ConclusionRNF216 is strongly upregulated in various tumors, including LIHC, and plays an extremely important role in tumor diagnosis and prognosis. Targeted knockout of RNF216 is beneficial for improving the efficacy of immunotherapy and chemotherapy.

Background: Colorectal cancer (CRC) has emerged as the third most prevalent malignancy worldwide. The pursuit of dependable molecular signatures stands as a crucial endeavor for tailoring treatment approaches, refining prognostic assessments, and heightening therapeutic efficacy in CRC management. This investigation was conducted to elucidate essential genes and molecular mechanisms associated with ferroptosis in CRC through implementing machine-learning approaches and AUcell analysis.Methods: The GEO repository and FerrDb served as primary sources for extracting information of gene sets on colorectal cancer and iron-dependent cell death mechanisms. To determine potential therapeutic targets with biomarker significance, we implemented LASSO and SVM-RFE methodology. The immune infiltrates were characterized followed by a competing endogenous RNA network analysis. The AUCell R package was utilized to examine the targeted gene activity patterns within individual cell lines using single-cell transcriptome data. The qRT-PCR and Human Protein Atlas (THPA) database were used to validate the expression of target genes. Potential therapeutic were explored through the DGIdb database.Results: Through the application of machine learning methodologies, five genes were identified as pivotal biomarker candidates: AQP8, NOX4, NR5A2, SCD, and TIMP1. The result of AUcell algorithm showed that the distribution of AUC values exhibited a bimodal pattern, with 2733 cells demonstrating elevated AUC values above the threshold of 0.091. The result of qRT-PCR showed that NOX4, SCD, and TIMP1 were significantly upregulated, while the expression of AQP8 and NR5A2 did not exhibit the expected differences. Both mRNA and IHC analyses from HPA database confirmed the abnormal expression of these pivotal candidate biomarkers. Algorithmic assessment via CIBERSORT methodology revealed notable shifts in immune cell composition within the tumor microenvironment of individuals diagnosed with CRC. Furthermore, A competing endogenous RNA network and 51 potential drug candidates were identified.Conclusion: A systematic framework implementing machine-learning approaches and AUcell analysis was established for identifying core ferroptosis genes and validating their functional link to ferroptosis. Meanwhile, a reliable ferroptosis-associated signature was established, which shed new light on the ferroptosis-mediated molecular mechanisms and therapeutic potential underlying CRC.

Cancer stem cells (CSCs) play pivotal roles in tumor relapse, metastasis, and therapy resistance. Interleukin 17 receptor A (IL-17RA) is a key mediator in colorectal cancer (CRC) pathogenesis and progression. Our recent study demonstrated that reduced IL-17RA expression correlates with favorable prognosis in CRC patients and suppresses tumor growth in murine models. This study aimed to investigate the role of IL-17RA in promoting cancer stem-like properties and its impact on colorectal cancer prognosis and chemoresistance. Expression levels of IL-17RA and CSC markers in CRC cells were evaluated using quantitative real-time polymerase chain reaction and Western blotting. Kaplan-Meier analysis of 68 CRC patients revealed that high IL-17RA expression is associated with poor clinical outcomes. To investigate IL-17RA's functional role, CRC cells with stable IL-17RA overexpression were analyzed for changes in CSC marker expression, sphere formation, and 5-fluorouracil (5-FU) resistance. IL-17RA overexpression significantly increased CSC marker expression, including cluster of differentiation 133 (CD133), leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), sex determining region Y-box 2 (SOX2), and enhanced tumor sphere formation and 5-FU resistance in SW620 cells. Specific inhibitors of IL-17RA signaling, such as the STAT3 inhibitor Stattic, reduced the expression of CD133, LGR5, ALDHA1, SOX2 and c-MYC, as well as tumor sphere formation in SW620 cells. These findings elucidate a novel IL-17RA-STAT3 axis that regulates CSC properties in CRC and highlight IL-17RA as a promising prognostic biomarker and therapeutic target for CRC treatment.

Glioblastomas represent the most prevalent primary brain tumors in adults. Due to their highly malignant biological behavior, they are classified as grade 4 according to the World Health Organization (WHO) classification of brain tumors. Despite the progress in understanding the molecular pathogenesis of these tumors, no curative therapy has been developed for patients with glioblastoma. In this study, an integrated comparative analysis of cyclin-dependent kinase inhibitor (CDKN) 2A/B chromosomal deletion was performed on 45 glioblastomas, representing the most frequent molecular subtypes of glioblastomas, receptor tyrosine kinase (RTK) I (n=13), RTK II (n=15), and the mesenchymal subtype (MES) (n=17). The analysis of copy number variation (CNV) profiles was conducted on CDKN2A/B losses. Subsequent statistical analysis was then applied to correlate the collected data with molecular glioblastoma epigenotypes. Loss of CDKN2A/B was found 44% (20/45) of all glioblastomas, thereby, in 46% (6/13) of RTK I, 67% (10/15) RTK II, and 24% (4/17) of MES. Statistical analysis showed that loss of CDKN2A/B is significant (p < 0.01) in RTK II compared with MES. Even though CDKN2A/B does not per se function as a molecular target, there is great potential for enhancing treatment outcomes through the restoration of the tumor-suppressing capabilities of CDKN2A/B. This strategy can be employed in therapeutic interventions and is a promising avenue for research. This efficacy of this approach demonstrates high potential, as evidenced by its efficacy in other tumors, including melanoma.

Sulforaphane-cysteine (SFN-Cys) is a naturally-occurring form of plant-derived isothiocyanate metabolites that displays several tumor-suppressive properties. However, the oncostatic potential of SFN-Cys on oral squamous cell carcinoma (OSCC) is mostly elusive. In this study, we tried to test whether SFN-Cys affects OSCC to progress and further explored the underlying array of molecular cues that SFN-Cys mediates. Our results demonstrate that SFN-Cys was an effective inducer of cytotoxicity to OSCC cells, accompanied with blockage of cell cycling and promotion of apoptotic events. Moreover, treatment of OSCC cells with SFN-Cys attuned an apoptosis-associated protein regulatory program, underlined by downregulation of apoptosis suppressors (cIAP-1 and XIAP) and activation of caspase cascades. Furthermore, caspase activations in SFN-Cys-treated OSCC cells were affected by the pre-incubation with a specific c-Jun N-terminal kinase (JNK) inhibitor, suggesting a functional link of JNK pathway to SFN-Cys's actions in OSCC cells. Collectively, our data revealed that SFN-Cys hampered cell cycle progression and elicited apoptotic responses in OSCC via a JNK-mediated activation of caspase pathways. These findings provide possible avenues for the application of a natural compound in the management of oral malignancies.

Thyroid carcinoma (TC) is the most prevalent malignancy of the endocrine system, with its incidence rising annually worldwide. Post-translational modifications and epigenetic changes have been documented to be pivotal in the initiation, progression, and malignant transformation of TC. In addition to mediating biological processes such as cell recognition, signal transduction, and immune regulation, these modifications can also significantly impact the development and metastasis of various cancers. Among these, sialylation is identified as a key post-translational modification, showing close associations with the invasiveness and metastatic potential of TC. This review aims to provide an overview of the current understanding of sialylation in TC, highlighting its underlying mechanisms and examining its roles in cell proliferation, invasion, and immune evasion. Additionally, this study intends to explore the potential of targeting sialylation as a novel therapeutic approach, providing new perspectives for TC prevention and treatment, as well as the development of new therapeutic agents.

Gastrointestinal tumors are among the most common tumors worldwide and are currently the leading cause of cancer-related deaths. Gastrointestinal tumors affect the digestive system and include esophageal, liver, gastric, colorectal, and pancreatic cancers. Aerobic glycolysis is a widespread phenomenon among gastrointestinal tumor cells, which poses a major hazard to human health and life. Increasing evidence suggests that aerobic glycolysis can induce and promote the development of gastrointestinal tumors by rapidly providing large amounts of energy and altering the tumor microenvironment. Among them, glucose transporter proteins and key enzymes involved in glycolysis are expressed at higher levels during aerobic glycolysis, and the corresponding signaling pathways and transcription regulatory factors are activated, playing an important role in the occurrence and development of tumors. Additionally, evidence has indicated that aerobic glycolysis plays an essential role in inhibiting the development of immune cells, modifying the population of immune cells present in the surrounding tumor, and promoting the polarization of immune cells. Moreover, drugs and compounds that target essential enzymes and transcription factors associated with glycolysis are known to exhibit anticancer properties.

Background: Pancreatic neuroendocrine tumors (PanNETs) are rare neoplasms with an increasing incidence. This study aims to validate the clinical relevance of the WHO 2017 classification system in the Taiwanese population and identify independent prognostic factors for patients with PanNETs.Materials and methods: We conducted a retrospective analysis of 176 patients with PanNETs from the Chang Gung Medical Hospital at Linkou in Taiwan, spanning the years 2009 to 2022. Pathology reports were reassessed according to the WHO 2017 classification. Clinical characteristics, treatment patterns, and survival outcomes were documented, with subgroup analyses to compare grade 3 (G3) neuroendocrine tumors and neuroendocrine carcinomas (NEC).Results: The overall 5-year survival rate was 58.7%, with median survival of 107.6 months. Survival rates showed clear stratification across WHO 2017 classifications: G1 (83.1%, median 141.0 months), G2 (55.0%, median 105.2 months), G3 (14.6%, median 21.5 months), and NEC (9.4%, median 19.6 months). Multivariate analysis identified five independent prognostic factors: age over 60 years (HR 1.70), tumor size >2cm (HR 1.893), lymph node involvement (HR 1.801), distant metastasis (HR 3.042), and NEC classification (HR 2.382). NEC demonstrated significantly higher lymph node involvement (81% vs 48%, p=0.026), higher Ki-67 index (69 vs 43.8, p<0.001), and higher rates of metastases compared with G3 NET.Conclusions: Our findings validate the prognostic utility of the WHO 2017 classification, particularly in differentiating NET G3 from NEC. This refined classification system, combined with identified prognostic factors, provides valuable guidance for clinical decision-making and treatment selection in patients with PanNETs.

Distinct from apoptosis, ferroptosis is intricately associated with intracellular iron ions and oxidative stress, representing a unique form of cell demise. In the treatment of ovarian cancer (OC), it assumes a crucial role, as research suggests its association with patient prognosis. This investigation delves into the correlation between genes associated with ferroptosis and the prognosis of OC, providing insights into its pathogenesis. Through the examination of mRNA expression using TCGA, ICGC, and GTEx databases, we identified a set of five pivotal genes (CD44, FTH1, ALOX12, SLC7A11, CRYAB) forming a prognostic model. Their regulation affects various aspects of OC, including the cell cycle, proliferation, invasiveness, immune response, and drug tolerance. To summarize, ferroptosis significantly impacts the prognosis of OC, and the targeting of relevant pathways holds potential for enhancing treatment outcomes, thereby guiding future research and personalized therapeutic strategies.