Oncology Research最新文献

Objective: Gastric cancer (GC) is a globally common cancer characterized by high incidence and mortality worldwide. Advances in the molecular understanding of GC provide promising targets for GC diagnosis and therapy. Long non-coding RNAs (lncRNAs) and their downstream regulators are regarded to be implicated in the progression of multiple types of malignancies. Studies have shown that the lncRNA small nucleolar RNA host gene 4 (SNHG4) serves as a tumor promoter in various malignancies, while its function in GC has yet to be characterized. Therefore, our study aimed to explore the role and underlying mechanism of SNHG4 in GC.

Methods: We used qRT-PCR to analyze SNHG4 expression in GC tissues and cells. Kaplan-Meier analysis was used to assess the correlation between SNHG4 expression and the survival rate of GC patients. Cellular function experiments such as CCK-8, BrdU, colony formation, flow cytometry analysis, and transwell were performed to explore the effects of SNHG4 on GC cell proliferation, apoptosis, cell cycle, migration, and invasion. We also established xenograft mouse models to explore the effect of SNHG4 on GC tumor growth. Mechanically, dual luciferase reporter assay was used to verify the interaction between SNHG4 and miR-409-3p and between miR-409-3p and cAMP responsive element binding protein 1 (CREB1).

Results: The results indicated that SNHG4 was overexpressed in GC tissues and cell lines, and was linked with poor survival rate of GC patients. SNHG4 promoted GC cell proliferation, migration, and invasion while inhibiting cell apoptosis and cell cycle arrest in vitro. The in vivo experiment indicated that SNHG4 facilitated GC tumor growth. Furthermore, SNHG4 was demonstrated to bind to miR-409-3p. Moreover, CREB1 was directly targeted by miR-409-3p. Rescue assays demonstrated that miR-409-3p deficiency reversed the suppressive impact of SNHG4 knockdown on GC cell malignancy. Additionally, miR-409-3p was also revealed to inhibit GC cell proliferation, migration, and invasion by targeting CREB1.

Conclusion: In conclusion, we verified that the SNHG4 promoted GC growth and metastasis by binding to miR-409-3p to upregulate CREB1, which may deepen the understanding of the underlying mechanism in GC development.

Background: As a novel blocker of vascular endothelial growth factor receptor (VEGFR), fruquintinib has been approved for treating colorectal cancer (CRC). However, its dosage and therapeutic efficacy are limited by its widespread adverse reactions. Venetoclax, recognized as the initial inhibitor of B-cell lymphoma protein 2 (BCL2), has shown potential in boosting the effectiveness of immunotherapy against CRC. This study investigated the efficacy and mechanisms of fruquintinib combined with venetoclax in treating CRC.

Methods and materials: We developed a colon cancer mouse model with the CT26 colon cell line to demonstrate fruquintinib and venetoclax's efficacy against tumors. Then we employed various techniques to evaluate different aspects of the experimental outcomes. Immunohistochemistry was used to detect cell proliferation and angiogenesis in tumor tissues. Western blot analysis was utilized to examine the occurrence of cell apoptosis, and flow cytometry to quantitate immune cells within the tumor tissues. Moreover, immunofluorescence was employed to measure cytokine levels.

Results: The strongest inhibition on tumor growth was achieved by the combination of fruquintinib with venetoclax, as opposed to individual drug use. Venetoclax was found to amplify the impact of fruquintinib, leading to decreased cancer cell proliferation, increased cancer cell apoptosis, lowered angiogenesis, better vascular structure normalization, and improved immune cell infiltration.

Conclusion: Our findings indicate that the addition of venetoclax enhances the impact of fruquintinib on vascular normalization and modulation of the tumor immune microenvironment. Our study presents the justification for utilizing the fruquintinib and venetoclax combination in treating CRC. Venetoclax holds promise in being assimilated into anticancer medications for CRC.

Background: Platinum chemotherapy (CT) remains the backbone of systemic therapy for patients with small-cell lung cancer (SCLC). The nucleotide excision repair (NER) pathway plays a central role in the repair of the DNA damage exerted by platinum agents. Alteration in this repair mechanism may affect patients' survival.

Materials and methods: We conducted a retrospective analysis of data from 38 patients with extensive disease (ED)-SCLC who underwent platinum-CT at the Clinical Oncology Unit, Careggi University Hospital, Florence (Italy), from 2015 to 2020. mRNA expression analysis and single nucleotide polymorphism (SNP) characterization of three NER pathway genes-namely ERCC1, ERCC2, and ERCC5-were performed on patient tumor samples.

Results: Overall, elevated expression of ERCC genes was observed in SCLC patients compared to healthy controls. Patients with low ERCC1 and ERCC5 expression levels exhibited a better median progression-free survival (mPFS = 7.1 vs. 4.9 months, p = 0.39 for ERCC1 and mPFS = 6.9 vs. 4.8 months, p = 0.093 for ERCC5) and overall survival (mOS = 8.7 vs. 6.0 months, p = 0.4 for ERCC1 and mOS = 7.2 vs. 6.2 months, p = 0.13 for ERCC5). Genotyping analysis of five SNPs of ERCC genes showed a longer survival in patients harboring the wild-type genotype or the heterozygous variant of the ERCC1 rs11615 SNP (p = 0.24 for PFS and p = 0.14 for OS) and of the rs13181 and rs1799793 ERCC2 SNPs (p = 0.43 and p = 0.26 for PFS and p = 0.21 and p = 0.16 for OS, respectively) compared to patients with homozygous mutant genotypes.

Conclusions: The comprehensive analysis of ERCC gene expression and SNP variants appears to identify patients who derive greater survival benefits from platinum-CT.

Background: Aberrant expression of RNA-binding proteins (RBPs) has been linked to a variety of diseases, including hematological disorders, cardiovascular diseases, and multiple types of cancer. Heterogeneous nuclear ribonucleoprotein C (HNRNPC), a member belonging to the heterogeneous nuclear ribonucleoprotein (hnRNP) family, plays a pivotal role in nucleic acid metabolism. Previous studies have underscored the significance of HNRNPC in tumorigenesis; however, its specific role in malignant tumor progression remains inadequately characterized.

Methods: We leveraged publicly available databases, including The Cancer Genome Atlas (TCGA), to explore the potential involvement of HNRNPC across various cancers. Additionally, we performed experimental validation studies focused on liver cancer.

Results: Our analysis revealed that HNRNPC is overexpressed in a wide range of common malignancies, including liver and lung cancers, and is strongly linked to unfavorable outcomes. Furthermore, HNRNPC was observed to be closely linked to tumor immunity. Through immune checkpoint analysis and immune cell infiltration assessment, HNRNPC emerged as a potential target for modulating tumor immunotherapy. Notably, silencing of HNRNPC markedly inhibited the proliferation, metastasis, and infiltration of liver cancer cells.

Conclusion: In summary, our findings highlight HNRNPC as a prognostic marker in various cancers, including liver cancer, and suggest its involvement in shaping the tumor immune microenvironment. These insights offer potential avenues for improving clinical outcomes in tumors with elevated HNRNPC expression, particularly through immunotherapeutic strategies.

Background: Triple-negative breast cancer (TNBC), characterized by its lack of traditional hormone receptors and HER2, presents a significant challenge in oncology due to its poor response to conventional therapies. Autophagy is an important process for maintaining cellular homeostasis, and there are currently autophagy biomarkers that play an effective role in the clinical treatment of tumors. In contrast to targeting protein activity, intervention with protein-protein interaction (PPI) can avoid unrelated crosstalk and regulate the autophagy process with minimal interference pathways.

Methods: Here, we employed Naive Bayes, Decision Tree, and k-Nearest Neighbors to elucidate the complex PPI network associated with autophagy in TNBC, aiming to uncover novel therapeutic targets. Meanwhile, the candidate proteins interacting with Beclin 2 were initially screened in MDA-MB-231 cells using Beclin 2 as bait protein by immunoprecipitation-mass spectrometry assay, and the interaction relationship was verified by molecular docking and CO-IP experiments after intersection. Colony formation, cellular immunofluorescence, cell scratch and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) tests were used to predict the clinical therapeutic effects of manipulating candidate PPI.

Results: By developing three PPI classification models and analyzing over 13,000 datasets, we identified 3733 previously unknown autophagy-related PPIs. Our network analysis revealed the central role of Beclin 2 in autophagy regulation, uncovering its interactions with 39 newly identified proteins. Notably, the CO-IP studies identified the substantial interaction between Beclin 2 and Ubiquilin 1, which was anticipated by our model and discovered in immunoprecipitation-mass spectrometry assay results. Subsequently, in vitro investigations showed that overexpressing Beclin 2 increased Ubiquilin 1, promoted autophagy-dependent cell death, and inhibited proliferation and metastasis in MDA-MB-231 cells.

Conclusions: This study not only enhances our understanding of autophagy regulation in TNBC but also identifies the Beclin 2-Ubiquilin 1 axis as a promising target for precision therapy. These findings open new avenues for drug discovery and offer inspiration for more effective treatments for this aggressive cancer subtype.

Background: Gastric cancer (GC) remains a global health burden and is often characterized by heterogeneous molecular profiles and resistance to conventional therapies. The phosphoinositide 3-kinase and PI3K and Janus kinase (JAK) signal transducer and activator of transcription (JAK-STAT) pathways play pivotal roles in GC progression, making them attractive targets for therapeutic interventions.

Methods: This study applied a computational and molecular dynamics simulation approach to identify and characterize SBL-JP-0004 as a potential dual inhibitor of JAK2 and PI3KCD kinases. KATOIII and SNU-5 GC cells were used for in vitro evaluation.

Results: SBL-JP-0004 exhibited a robust binding affinity for JAK2 and PI3KCD kinases, as evidenced by molecular docking scores and molecular dynamics simulations. Binding interactions and Gibbs binding free energy estimates confirmed stable and favorable interactions with target proteins. SBL-JP-0004 displayed an half-maximal inhibitory concentration (IC₅₀) value of 118.9 nM against JAK2 kinase and 200.9 nM against PI3KCD enzymes. SBL-JP-0004 exhibited potent inhibition of cell proliferation in KATOIII and SNU-5 cells, with half-maximal growth inhibitory concentration (GI₅₀) values of 250.8 and 516.3 nM, respectively. A significant elevation in the early phase apoptosis (28.53% in KATOIII cells and 26.85% in SNU-5 cells) and late phase apoptosis (17.37% in KATOIII cells and 10.05% in SNU-5 cells) were observed with SBL-JP-0004 treatment compared to 2.1% and 2.83% in their respective controls.

Conclusion: The results highlight SBL-JP-0004 as a promising dual inhibitor targeting JAK2 and PI3KCD kinases for treating GC and warrant further preclinical and clinical investigations to validate its utility in clinical settings.

Background: Head and neck squamous cell carcinoma (HNSCC) is a prevalent form of cancer globally, with chemoresistance posing a major challenge in treatment outcomes. The efficacy of the commonly used chemotherapeutic agent, cisplatin, is diminished in patients with poor prognoses.

Methods: Various bioinformatics databases were utilized to examine Carboxylesterase 1 (CES1) gene expression, clinicopathologic features, patient survival analysis, and gene function. An organoid model of HNSCC was established, along with the induction of drug-resistant HNSCC in the organoid model. CES1 expression was assessed using qRT-PCR and Western Blot, and differential markers were identified through transcriptome sequencing. Knockdown and overexpression models of CES1 were created in SCC-9 and patient-derived organoid (PDO) cells using shRNA and lentivirus to investigate the tumor biology and cisplatin resistance associated with CES1.

Results: Research in bioinformatics has uncovered a strong correlation between the expression level of CES1 and the prognosis of HNSCC. The data suggests a significant link between CES1 expression and tobacco smoking. RNA-sequencing revealed a notable increase in CES1 expression in HNSCC-PDO^cis-R cells compared to the parental PDO cells. Subsequently, we performed in vitro studies by HNSCC-PDO and SCC-9 and found that CES1-overexpressing cells exhibited reduced sensitivity to cisplatin and stronger tumor malignant biological behavior compared with CES1-knockdown cells.

Conclusion: The observed association between CES1 expression and tobacco smoking implies a potential influence of smoking on the efficacy of cisplatin-based chemotherapy in HNSCC through the regulation of CES1 expression.

Background: Drug resistance is the main factor contributing to cancer recurrence and poor prognosis. Exploration of drug resistance-related mechanisms and effective therapeutic targets are the aim of molecular targeted therapy. In our study, the role of long non-coding RNA (lncRNA) AFAP1-AS1 in gemcitabine resistance and related mechanisms were explored in cervical cancer cells.

Methods: Gemcitabine-resistant cervical cancer cell lines HT-3-Gem and SW756-Gem were constructed using the gemcitabine concentration gradient method. The overall survival rates and recurrence-free survival rates were evaluated by Kaplan-Meier analysis. The interaction was verified through a Dual-luciferase reporter gene assay and a Biotinylated RNA pull-down assay. Cell proliferation ability was assessed through methyl-thiazolyl-tetrazolium (MTT), soft agar, and colony formation experiments. Cell cycle and apoptosis were detected by flow cytometry.

Results: Up-regulation of AFAP1-AS1 in cervical cancer predicted a poor prognosis. Besides, patients in the gemcitabine-resistance group had higher levels of AFAP1-AS1 than the gemcitabine-sensitive group. AFAP1-AS1 promoted tumor growth and induced gemcitabine tolerance of cervical cancer cells. In addition, AFAP1-AS1 mediated epidermal growth factor receptor (EGFR) expression by serving as a molecular sponge for microRNA-7a-5p (miR-7-5p). This present study also proved that the knockdown of EGFR or overexpression of miR-7a-5p abolished the accelerative role of AFAP1-AS1 overexpression in cancer progression and gemcitabine tolerance.

Conclusions: In general, the AFAP1-AS1/miR-7-5p/EGFR axis was tightly related to the progression and gemcitabine tolerance of cervical cancer, providing potential targets for the management of cervical cancer.

Background: Polymethoxylated flavones (PMFs) are compounds present in citrus peels and other Rutaceae plants, which exhibit diverse biological activities, including robust antitumor and antioxidant effects. However, the mechanism of PMFs in reversing drug resistance to colon cancer remains unknown. In the present study, we aimed to investigate the potential connection between the aerobic glycolysis-ROS-autophagy signaling axis and the reversal of PTX resistance in colon cancer by PMFs.

Methods: MTT Cell viability assay and colony formation assay were used to investigate the effect of PMFs combined with PTX in reversing HCT8/T cell resistance ex vivo; the mRNA and protein levels of the target were detected by SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis), quantitative real-time fluorescence polymerase chain reaction (qRT-PCR) and Western blot protein immunoblotting (WB); An HCT8/T cell xenograft model was established to investigate the MDR reversal activity of PMFs in vivo; The extracellular acidification rate (ECAR) and the oxygen consumption rate (OCR) were detected to assess the cellular oxygen consumption rate and glycolytic process.

Results: HCT8/T cells demonstrated significant resistance to PTX, up-regulating the expression levels of ABCB1 mRNA, P-gp, LC3-I, and LC3-II protein, and increasing intracellular reactive oxygen species (ROS) content. PMFs mainly contain two active ingredients, nobiletin, and tangeretin, which were able to reverse drug resistance in HCT8/T cells in a concentration-dependent manner. PMFs exhibited high tolerance in the HCT8/T nude mouse model while increasing the sensitivity of PTX-resistant cells and suppressing tumor growth significantly. PMFs combined with PTX reduced extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) in HCT8/T cells. Additionally, PMFs reduced intracellular ROS content, down-regulated the expression levels of autophagy-related proteins LC3-I, LC3-II, Beclin1, and ATG7, and significantly reduced the number of autophagosomes in HCT8/T cells.

Conclusions: The present study demonstrated that PMFs could potentially reverse PTX resistance in colon cancer by regulating the aerobic glycolysis-ROS-autophagy signaling axis, which indicated that PMFs would be potential potentiators for future chemotherapeutic agents in colon cancer.

Background: The heterogeneity of prognosis and treatment benefits among patients with gliomas is due to tumor microenvironment characteristics. However, biomarkers that reflect microenvironmental characteristics and predict the prognosis of gliomas are limited. Therefore, we aimed to develop a model that can effectively predict prognosis, differentiate microenvironment signatures, and optimize drug selection for patients with glioma.

Materials and methods: The CIBERSORT algorithm, bulk sequencing analysis, and single-cell RNA (scRNA) analysis were employed to identify significant cross-talk genes between M2 macrophages and cancer cells in glioma tissues. A predictive model was constructed based on cross-talk gene expression, and its effect on prognosis, recurrence prediction, and microenvironment characteristics was validated in multiple cohorts. The effect of the predictive model on drug selection was evaluated using the OncoPredict algorithm and relevant cellular biology experiments.

Results: A high abundance of M2 macrophages in glioma tissues indicates poor prognosis, and cross-talk between macrophages and cancer cells plays a crucial role in shaping the tumor microenvironment. Eight genes involved in the cross-talk between macrophages and cancer cells were identified. Among them, periostin (POSTN), chitinase 3 like 1 (CHI3L1), serum amyloid A1 (SAA1), and matrix metallopeptidase 9 (MMP9) were selected to construct a predictive model. The developed model demonstrated significant efficacy in distinguishing patient prognosis, recurrent cases, and characteristics of high inflammation, hypoxia, and immunosuppression. Furthermore, this model can serve as a valuable tool for guiding the use of trametinib.

Conclusions: In summary, this study provides a comprehensive understanding of the interplay between M2 macrophages and cancer cells in glioma; utilizes a cross-talk gene signature to develop a predictive model that can predict the differentiation of patient prognosis, recurrence instances, and microenvironment characteristics; and aids in optimizing the application of trametinib in glioma patients.