Oncology Research最新文献

Background: Rho GTPases are essential regulators for cellular movement and intracellular membrane trafficking. Their enzymatic activities fluctuate between active GTP-bound and inactive GDP-bound states regulated by GTPase activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs). Arhgap39/Vilse/Porf-2 is a newly identified GAP. The role of Arhgap39 in migration and invasion has not been addressed thoroughly.

Methods: The Arhgap39 gene was knocked out by Crispr-Cas9 gene editing in mouse Hepa1-6 and Hepa-1c1c7 cells to analyze the impact of Arhgap39 depletion on migration and invasion.

Results: Loss of Arhgap39 noticeably increased the migration and invasive potential. Purified Arhgap39 recombinant protein facilitated the hydrolysis of GTP in RhoA and Rac1 in vitro. RNA-seq analysis revealed that matrix metalloproteinase 13 (MMP13) and Laminin subunit beta 1 (LAMB1) were increased in Arhgap39^-/- cells. We further crossed Arhgap39fl/fl with KrasLSL-G12D and p53fl/fl mice under the control of albumin-Cre recombinase to induce the spontaneous development of hepatocellular carcinomas. Intriguingly, the expression levels of MMP13 and the overall survival in Alb-Cre_KrasLSL-G12D_p53fl/fl_Arhgap39fl/fl (KPA) mice were comparable to control Alb-Cre_KrasLSL-G12D_p53fl/fl (KP) mice. The cell migration and invasion of KPA mice were also similar to those of control KP mice.

Conclusion: Arhgap39 loss could modulate the migration and invasion in some hepatocellular cancer cells, but not in those isolated from KPA mice.

Objectives: Melanoma is a highly aggressive and metastatic form of cancer, and the role of exosomal microRNAs (miRNAs) in its progression remains largely unexplored. This study aimed to investigate the effects of melanoma cell-derived exosomal miR-424-5p on angiogenesis and its underlying mechanisms.

Methods: Exosomes were isolated from melanoma cell lines A375 and A2058, and their effects on the proliferation, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs) were examined. The interaction between miR-424-5p and its target gene, large tumor suppressor kinase 2 (LATS2), was analyzed using luciferase reporter assays and functional experiments. In vivo, tumor growth and angiogenesis were studied in a xenograft model using nude mice.

Results: Melanoma cell-derived exosomes could be internalized by HUVECs, which promoted proliferation, migration, and angiogenesis. miR-424-5p was highly expressed in melanoma cells and their exosomes, and its inhibition in exosomes suppressed HUVEC proliferation, migration, and angiogenesis. LATS2 was identified as a direct target of miR-424-5p, and its silencing reversed the inhibitory effects of miR-424-5p inhibition on HUVEC functions. In vivo, exosomes derived from miR-424-5p-inhibited melanoma cells suppressed tumor growth and angiogenesis in xenograft models.

Conclusions: Melanoma cell-derived exosomal miR-424-5p promotes angiogenesis by targeting LATS2, contributing to melanoma progression. Targeting the exosomal miR-424-5p/LATS2 axis could be a potential therapeutic strategy for melanoma.

Background: PLK3, which played an important role in cell cycle progression and stress response, was identified as highly expressed in various carcinomas. However, the functions, molecular characteristics, and prognostic value of PLK3 in glioma remained unexplored.

Methods: We analyzed PLK3 expression in glioma samples from multiple databases. Both overexpression and knockdown of Plk3 were performed to investigate tumor cell growth in glioma, and the transplanted glioma mouse model demonstrated the role of Plk3 on tumor progression. Immunohistochemistry was conducted to detect PLK3 expression and immune cell infiltration. The trans-well assay for PLK3 on the immune cells recruitment was also determined. Additionally, we further evaluated the correlation between PLK3 and PD-1/PD-L1 as well as other immune checkpoints.

Results: We found that an increased level of PLK3 was associated with malignancy and poor prognosis of glioma, and further validated that PLK3 promoted glioma progression. PLK3 also played a crucial role in immune response and was involved in Tcell immune suppression. Specifically, we revealed that CD8⁺ and CD4⁺ Tcell infiltration was decreased in Plk3 overexpressed xenografts. Furthermore, it was predicted that PLK3 was synergistic with other checkpoint members in glioma. In general, high expression of PLK3 was associated with a malignant process and poor prognosis in glioma patients.

Conclusion: Our findings indicated that PLK3 expression level was highly correlated to the malignancy of gliomas, and we validated that PLK3 could promote the GBM progress in vitro and in vivo. Furthermore, PLK3 played important roles in Tcell and neutrophil immune response in glioma. Besides, the conspicuous association between PLK3 and other immune checkpoints was also observed. Crucially, high-level PLK3 expression was revealed to be related to poor clinical prognosis. These results demonstrated that PLK3 may serve as a prognostic biomarker and a potential target for glioma.

Background: The outcomes of pediatric patients with acute lymphoblastic leukemia (ALL) remain far less than favorable. While apigenin is an anti-cancer agent, studies on the mechanism by which it regulates ALL cell cycle progression are inadequate. Ferroptosis and AMP-activated protein kinase (AMPK) signaling are important processes for ALL patients. However, it remains unclear whether apigenin works by affecting AMPK and apoptosis.

Materials and methods: SUP-B15 and T-cell Jurkat ALL cells were treated with apigenin, and cell viability and apoptosis were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays, respectively. The thiobarbituric acid-reactive substances (TBARS) assay was used to evaluate lipid peroxidation. Intracellular Fe²⁺ levels were measured using a commercial kit. Corresponding proteins were detected by western blotting.

Results: Results showed that apigenin reduced cell viability and the levels of Ki67 and proliferating cell nuclear antigen (PCNA) expression in a concentration-dependent manner in both types of ALL cells. Apigenin also exerted anti-apoptotic effects on SUP-B15 and Jurkat cells. Apigenin activated AMP-activated protein kinase (AMPK) signaling and induced ferroptosis, and those effects were attenuated by inhibition of AMPK. Eventually, the reduced cell proliferation and increased cell apoptosis caused by apigenin in ALL cells were partly abolished by AMPK inhibition.

Conclusion: In summary, apigenin exerted anti-leukemia activity in ALL cells, and that effect was partially achieved by activation of AMPK signaling. Our findings suggest apigenin as a potential drug for treatment of ALL.

Objectives: KH-type splicing regulatory protein (KHSRP) is an RNA-binding protein involved in several cellular processes, including nuclear splicing, mRNA localization, and cytoplasmic degradation. While KHSRP's role has been studied in other cancers, its specific involvement in gastric cancer remains poorly understood. This study aims to explore KHSRP expression in gastric cancer and its potential effects on tumor progression and immune response.

Methods: KHSRP expression in gastric cancer tissues and normal tissues was analyzed using data from The Cancer Genome Atlas (TCGA) database. The correlation between KHSRP expression, patient survival, and immune response was also assessed. Immunohistochemistry was performed to evaluate KHSRP expression in gastric cancer tissues. Gain- and loss-of-function experiments were conducted to assess KHSRP's effects on gastric cancer cell proliferation, stemness, and migration. Furthermore, the impact of KHSRP silencing on tumor volume and immune cell infiltration was evaluated in a C3H/He mouse xenograft model.

Results: KHSRP was found to be overexpressed in gastric cancer tissues compared to normal tissues, with a positive correlation to tumor stage and a negative correlation with patient prognosis. Functional assays revealed that KHSRP promotes gastric cancer cell proliferation, enhances cancer stem cell properties, and increases migratory capabilities in vitro. In vivo, KHSRP silencing led to a significant reduction in tumor volume and increased immune cell infiltration in the mouse xenograft model.

Conclusions: KHSRP acts as an oncogene in gastric cancer by promoting tumorigenesis and suppressing anti-tumor immune responses. Its overexpression is associated with poor prognosis, making KHSRP a potential prognostic marker and therapeutic target in gastric cancer.

Background: Patients with gastric cancer (GC) are prone to lymph node metastasis (LNM), which is an important factor for recurrence and poor prognosis of GC. Nowadays, more and more studies have confirmed that exosomes can participate in tumor lymphangiogenesis. An in-depth exploration of the pathological mechanism in the process of LNM in GC may provide effective targets and improve the diagnosis and treatment effect.

Materials and methods: We used sequencing analysis of collected serum to screen out exo-miRNA related to LNM in GC. ELISA, qRT-PCR, Western Blot, RNA pull-down assay, Transwell assay, animal experiments, and other experiments were used to verify the results.

Results: In this study, we screened out miR-224-3p related to GC progression and LNM in a vascular endothelial growth Factor C (VEGFC)-independent manner. We found that exo-miR-224-3p derived from GC cells could enter human lymphatic endothelial cells (HLECs) and promote the tube formation and migration of HLECs. In addition, it was revealed that miR-224-3p could bind to the 3'UTR region of GSK3B mRNA. Then, we proved that inhibiting the expression of GSK3B could suppress the phosphorylation of β-catenin and promote the transcription of PROX1, thus leading to tumor lymphangiogenesis. Furthermore, it was also found that hnRNPA1 mediated the sorting of miR-224-3p into exosomes, and the high expression of PKM2 promoted the secretion of exo-miR-224-3p.

Conclusions: Our discovery of the exo-miR-224-3p/GSK3B/β-catenin/PROX1 axis may provide a new direction for the clinical treatment of GC.

Background: Sunitinib resistance is a major challenge in advanced renal cell carcinoma (RCC). Clinically, elucidating the underlying mechanisms and developing practical countermeasures for sunitinib resistance in RCC is desirable. In previous studies, we found that circAGAP1 expression was significantly upregulated in clear cell RCC (ccRCC) and was strongly associated with poor prognosis. However, the role of circAGAP1 in sunitinib resistance in ccRCC remains unclear.

Methods: We used public databases for bioinformatics analysis to identify the binding targets of circAGAP1. Additionally, the effects of circAGAP1 on the proliferation, clonogenesis, apoptosis, and migration of ccRCC cells were analyzed using quantitative real-time PCR, cell counting kit-8 assays, migration and apoptosis assays, and colony formation assays. Furthermore, RNA immunoprecipitation, dual-luciferase reporter, and fluorescence in situ hybridization assays were used to explore the molecular mechanism.

Results: In this study, circAGAP1 exhibited higher expression in sunitinib-sensitive ccRCC cells and inhibited the clonogenesis, proliferation, and migration of ccRCC cells after sunitinib treatment. Mechanical studies revealed that circAGAP1 regulated the expression of sunitinib target platelet-derived growth factor receptor by acting as a microRNA sponge that suppresses miR-149-5p, miR-455-5p, and miR-15a-5p simultaneously. Overexpression of these three miRNAs reversed circAGAP1-mediated sunitinib sensitivity in ccRCC.

Conclusions: In summary, our findings indicate that circAGAP1 may serve as a promising biomarker to predict sunitinib sensibility and a therapeutic target in ccRCC.

Background: EMP2 is a tumor-associated membrane protein belonging to the GAS-3/PMP22 gene family. EMP2 expression demonstrates significant tissue specificity and heterogeneity in various human tissues and tumor tissues, where it may play a role in either promoting or inhibiting tumor growth. This study aimed to investigate the expression level, biological functions, and molecular mechanisms of EMP2 in liver cancer.

Methods: we analyzed the mRNA expression levels of EMPs family genes in hepatocellular carcinoma (HCC) tissues and normal liver tissues based on the TCGA database and immunohistochemical analysis of tissue microarrays. Subsequently, we constructed HCC cell lines with either knockdown or overexpression of EMP2 to examine the biological functions and molecular mechanisms of EMP2 in tumorigenesis in vivo and in vitro.

Results: Bioinformatic and immunohistochemical analysis of tissue microarrays have confirmed the significant upregulation of EMP2 in HCC tissues. In vitro and in vivo studies have shown that downregulation of EMP2 results in a moderate reduction in the proliferation and invasive capacity of HCC cells. Conversely, overexpression of EMP2 enhances the invasive capacity of HCC cells and induces autophagy. Initial investigations into the molecular mechanisms underlying EMP2-mediated enhancement of HCC cell invasion have revealed the dual regulation of EMP2-induced autophagy and the integrin pathway, which synergistically influence the invasive and metastatic potential of HCC cells.

Conclusion: EMP2 holds promise as a diagnostic marker for HCC metastasis and a potential target for targeted therapy.

Background: Immune checkpoint inhibitors (ICIs) are effective in a subset of patients with metastatic solid tumors. However, the patients who would benefit most from ICIs in biliary tract cancer (BTC) are still controversial.

Materials and methods: We molecularly characterized tissues and blood from 32 patients with metastatic BTC treated with the ICI pembrolizumab as second-line therapy.

Results: All patients had microsatellite stable (MSS) type tumors. Three of the 32 patients achieved partial response (PR), with an objective response rate (ORR) of 9.4% (95% confidence interval [CI], 2.0-25.2) and nine showed stable disease (SD), exhibiting a disease control rate (DCR) of 37.5% (95% CI, 21.1-56.3). For the 31 patients who had access to PD-1 ligand 1 (PD-L1) combined positive score (CPS) testing (cut-off value ≥1%), the ORR was not different between those who had PD-L1-positive (PD-L1+; 1/11, 9.1%) and PDL1-(2/20, 10.0%) tumors (p = 1.000). The tumor mutational burden (TMB) of PD-L1+ BTC was comparable to that of PD-L1-BTC (p = 0.630). TMB and any exonic somatic mutations were also not predictive of pembrolizumab response. Molecular analysis of blood and tumor samples demonstrated a relatively high natural killer (NK) cell proportion in the peripheral blood before pembrolizumab treatment in patients who achieved tumor response. Moreover, the tumors of these patients presented high enrichment scores for NK cells, antitumor cytokines, and Th1 signatures, and a low enrichment score for cancer-associated fibroblasts.

Conclusions: This study shows the molecular characteristics associated with the efficacy of pembrolizumab in BTC of the MSS type.

Background: To investigate SCL/TAL 1 interrupting locus (STIL)'s role and prognostic significance in lung adenocarcinoma (LUAD) progression, we examined STIL and E2 promoter binding factor 1 (E2F1) expression and their impacts on LUAD prognosis using Gene Expression Profiling Interactive Analysis (GEPIA).

Methods: Functional assays including CCK-8, wound-healing, 5-ethynyl-2-deoxyuridine (EdU), Transwell assays, and flow cytometry, elucidated STIL and E2F1's effects on cell viability, proliferation, apoptosis, and migration. Gene set enrichment analysis (GSEA) identified potential pathways, while metabolic assays assessed glucose metabolism.

Results: Our findings reveal that STIL and E2F1 are overexpressed in LUAD, correlating with adverse outcomes. It enhances cell proliferation, migration, and invasion, and suppresses apoptosis, activating downstream of E2F1. Silencing E2F1 reversed the promotion effect of the STIL overexpression on cell viability and invasiveness. Importantly, STIL modulates glycolysis, influencing glucose consumption, lactate production, and energy balance in LUAD cells.

Conclusion: Our model, incorporating STIL, age, and disease stage, robustly predicts patient prognosis, underscored STIL's pivotal role in LUAD pathogenesis through metabolic reprogramming. This comprehensive approach not only confirms STIL's prognostic value but also highlights its potential as a therapeutic target in LUAD.