Oncology Research最新文献

Background: Caffeic acid (CA) is considered a promising phytochemical that has inhibited numerous cancer cell proliferation. Therefore, it is gaining increasing attention due to its safe and pharmacological applications. In this study, we investigated the role of CA in inhibiting the Interleukin-6 (IL-6)/Janus kinase (JAK)/Signal transducer and activator of transcription-3 (STAT-3) mediated suppression of the proliferation signaling in human prostate cancer cells.

Materials and methods: The role of CA in proliferation and colony formation abilities was studied using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay and colony formation assays. Tumour cell death and cell cycle arrest were identified using flow cytometry techniques. CA treatment-associated protein expression of mitogen-activated protein kinase (MAPK) families, IL-6/JAK/STAT-3, proliferation, and apoptosis protein expressions in PC-3 and LNCaP cell lines were measured using Western blot investigation.

Results: We have obtained that treatment with CA inhibits prostate cancer cells (PC-3 and LNCaP) proliferation and induces reactive oxygen species (ROS), cell cycle arrest, and apoptosis cell death in a concentration-dependent manner. Moreover, CA treatment alleviates the expression phosphorylated form of MAPK families, i.e., extracellular signal-regulated kinase 1 (ERK1), c-Jun N-terminal kinase (JNK), and p38 in PC-3 cells. IL-6 mediated JAK/STAT3 expressions regulate the proliferation and antiapoptosis that leads to prostate cancer metastasis and migration. Therefore, to mitigate the expression of IL-6/JAK/STAT-3 is considered an important target for the treatment of prostate cancer. In this study, we have observed that CA inhibits the expression of IL-6, JAK1, and phosphorylated STAT-3 in both PC-3 and LNCaP cells. Due to the inhibitory effect of IL-6/JAK/STAT-3, it resulted in decreased expression of cyclin-D1, cyclin-D2, and CDK1 in both PC-3 cells. In addition, CA induces apoptosis by enhancing the expression of Bax and caspase-3; and decreased expression of Bcl-2 in prostate cancer cells.

Conclusions: Thus, CA might act as a therapeutical application against prostate cancer by targeting the IL-6/JAK/STAT3 signaling axis.

Background: Dihydrolipoamide S-acetyltransferase (DLAT) is a subunit of the pyruvate dehydrogenase complex (PDC), a rate-limiting enzyme complex, that can participate in either glycolysis or the tricarboxylic acid cycle (TCA). However, the pathogenesis is not fully understood. We aimed to perform a more systematic and comprehensive analysis of DLAT in the occurrence and progression of tumors, and to investigate its function in patients' prognosis and immunotherapy.

Methods: The differential expression, diagnosis, prognosis, genetic and epigenetic alterations, tumor microenvironment, stemness, immune infiltration cells, function enrichment, single-cell analysis, and drug response across cancers were conducted based on multiple computational tools. Additionally, we validated its carcinogenic effect and possible mechanism in glioma cells.

Results: We exhibited that DLAT expression was increased in most tumors, especially in glioma, and affected the survival of tumor patients. DLAT was related to RNA modification genes, DNA methylation, immune infiltration, and immune infiltration cells, including CD4+ T cells, CD8+ T cells, Tregs, and cancer-associated fibroblasts. Single-cell analysis displayed that DLAT might regulate cancer by mediating angiogenesis, inflammation, and stemness. Enrichment analysis revealed that DLAT might take part in the cell cycle pathway. Increased expression of DLAT leads tumor cells to be more resistant to many kinds of compounds, including PI3Kβ inhibitors, PKC inhibitors, HSP90 inhibitors, and MEK inhibitors. In addition, glioma cells with DLAT silence inhibited proliferation, migration, and invasion ability, and promoted cell apoptosis.

Conclusion: We conducted a comprehensive analysis of DLAT in the occurrence and progression of tumors, and its possible functions and mechanisms. DLAT is a potential diagnostic, prognostic, and immunotherapeutic biomarker for cancer patients.

Background: Pancreatic ductal adenocarcinoma (PDAC) has a rich and complex tumor immune microenvironment (TIME). M2 macrophages are among the most extensively infiltrated immune cells in the TIME and are necessary for the growth and migration of cancers. However, the mechanisms and targets mediating M2 macrophage infiltration in pancreatic cancer remain elusive.

Methods: The M2 macrophage infiltration score of patients was assessed using the xCell algorithm. Using weighted gene co-expression network analysis (WGCNA), module genes associated with M2 macrophages were identified, and a predictive model was designed. The variations in immunological cell patterns, cancer mutations, and enrichment pathways between the cohorts with the high- and low-risk were examined. Additionally, the expression of FCGR3A and RNASE2, as well as their association with M2 macrophages were evaluated using the HPA, TNMplot, and GEPIA2 databases and verified by tissue immunofluorescence staining. Moreover, in vitro cell experiments were conducted, where FCGR3A was knocked down in pancreatic cancer cells using siRNA to analyze its effects on M2 macrophage infiltration, tumor proliferation, and metastasis.

Results: The prognosis of patients in high-risk and low-risk groups was successfully distinguished using a prognostic risk score model of M2 macrophage-related genes (p = 0.024). Between the high- and low-risk cohorts, there have been notable variations in immune cell infiltration patterns, tumor mutations, and biological functions. The risk score was linked to the manifestation of prevalent immunological checkpoints, immunological scores, and stroma values (all p < 0.05). In vitro experiments and tissue immunofluorescence staining revealed that FCGR3A can promote the infiltration or polarization of M2 macrophages and enhance tumor proliferation and migration.

Conclusions: In this study, an M2 macrophage-related pancreatic cancer risk score model was established, and found that FCGR3A was correlated with tumor formation, metastasis, and M2 macrophage infiltration.

Objectives: The Kirsten rat sarcoma virus (KRAS) G12D oncogenic mutation poses a significant challenge in treating solid tumors due to the lack of specific and effective therapeutic interventions. This study aims to explore innovative approaches in T cell receptor (TCR) engineering and characterization to target the KRAS G12D_7-16 mutation, providing potential strategies for overcoming this therapeutic challenge.

Methods: In this innovative study, we engineered and characterized two T cell receptors (TCRs), KDA11-01 and KDA11-02 with high affinity for the KRAS G12D_7-16 mutation. These TCRs were isolated from tumor-infiltrating lymphocytes (TILs) derived from tumor tissues of patients with the KRAS G12D mutation. We assessed their specificity and anti-tumor activity in vitro using various cancer cell lines.

Results: KDA11-01 and KDA11-02 demonstrated exceptional specificity for the HLA-A*11:01-restricted KRAS G12D_7-16 epitope, significantly inducing IFN-γ release and eliminating tumor cells without cross-reactivity or alloreactivity.

Conclusions: The successful development of KDA11-01 and KDA11-02 introduces a novel and precise TCR-based therapeutic strategy against KRAS G12D mutation, showing potential for significant advancements in cancer immunotherapy.

Background: This article aims to present the single-institution outcomes of patients with Fibrolamellar Carcinoma (FLC) treated with liver-directed therapies (LDT).

Methods: In this single-center retrospective study, all patients diagnosed with FLC who underwent LDT were identified. Between July 2012 and July 2023, six patients were identified. One patient was excluded due to bleeding. Demographic and clinical parameters were recorded. Complications within 30 days of the LDT were evaluated. Radiological treatment responses at 1, 6, and 12 months were assessed per mRECIST.

Results: A total of five patients, which included three females and two males, were reviewed. Three patients were treated with transarterial hepatic embolization (TAE; n = 3), transarterial radioembolization (TARE; n = 1), and combined TAE + radiofrequency ablation (n = 1). The objective response rate at one month was 80% [CR = 2 (40%), PR = 2 (40%), and SD = 1 (20%)]. At 12 months (n = 4), two patients demonstrated CR (50%) and two demonstrated PR (50%). Overall survival from LDT at five years was 50%. There was no 30-day mortality among this group of patients or any adverse event attributable to the LDT.

Conclusion: TAE, TARE, and ablation are safe and effective therapeutic options for FLC. Based on this study and previously published case reports, ablation and TARE yielded the most favorable results.

Background: Glioblastoma remains a highly invasive primary brain malignancy with an undesirable prognosis. Growing evidence has shed light on the importance of microRNAs (miRs), as small non-coding RNAs, in tumor development and progression. The present study leverages the in-silico and in-vitro techniques to investigate the significance of hsa-miR-181a-5p and the underlying hsa-miR-181a-5p-meidated signaling pathway in glioblastoma development.

Methods: Bioinformatic studies were performed on GSE158284, GSE108474 (REMBRANDT study), TCGA-GTEx, CCLE, GeneMANIA, Reactome, WikiPathways, KEGG, miRDB, and microT-CDS to identify the significance of hsa-miR-181a-5p and its underlying target. Afterward, the U373 cell line was selected and transfected with hsa-miR-181a-5p mimics, and the cell viability, clonogenicity, migration, mRNA expression, apoptosis, and cell cycle were studied using the MTT assay, colony formation test, migration assay, qRT-PCR, and flow cytometry respectively.

Results: hsa-miR-181a-5p expression is decreased in glioblastoma samples. The in-silico results have shown that hsa-miR-181a-5p could regulate the MAPK pathway by targeting AKT3. The experimental assays have shown that hsa-miR-181a-5p decreases the migration of glioblastoma cells, arrests the cell cycle, and increases the apoptosis rate. Besides downregulating MMP9 and upregulating BAX, hsa-miR-181a-5p downregulates MET, MAP2K1, MAPK1, MAPK3, and AKT3 expression in U373 cells. The in-vitro results were consistent with in-silico results regarding the regulatory effect of hsa-miR-181a-5p on the MAPK pathway, leading to tumor suppression in glioblastoma.

Conclusions: hsa-miR-181a-5p inhibits glioblastoma development partially by regulating the signaling factors of the MAPK pathway.

[This retracts the article DOI: 10.3727/096504017X15144755633680.].

[This retracts the article DOI: 10.3727/096504018X15166193231711.].

Background: Lung cancer (LC) is one of the most common neoplastic diseases and a leading cause of death in Saudi Arabia. Its incidence in Saudi Arabia has increased by more than 3% within two decades. Our study aimed to describe the epidemiological and genetic landscapes of LC in Al-Madinah city in Saudi Arabia.

Methods: A retrospective analysis was conducted on the medical records of 65 patients diagnosed with lung cancer between 2015 and 2021 at a single medical oncology center in Al-Madinah city of Saudi Arabia.

Results: The mean patients' age was 59.2 years, with 50 (76.9%) males and 15 (23.1%) females; 37 (57%) smokers, and 28 (43%) non-smokers. The number of cases per year has increased gradually over six years from 2015 (n = 3) to 2020 (n = 13). The most prevalent histopathological diagnosis was non-small cell lung cancer (NSCLC) (n = 58, 89%) followed by small cell lung cancer (SCLC) (n = 5, 7.8%). NSCLC was frequently more common in smokers while squamous cell carcinoma was more frequent in non-smokers. Around 89% (n = 58) of the cases were diagnosed in late stage IV and the most common metastatic sites were to pleura and lymph nodes (n = 32, 49.2%). Program Death Legend-1 (PDL-1) was fairly expressed in 7/10 (70%) patients. Epidermal Growth Factor Receptor (EGFR) was mutated in 5/17 (29%) patients. Other mutations detected include Anaplastic Lymphoma Kinase (ALK) and phosphatidylinositol 3-kinase (PIK3C) mutations in two patients.

Conclusions: Our study revealed that lung cancer is a significant burden in Al-Madinah city of Saudi Arabia. If the risk factors are not controlled, the number of cases may increase considerably. Health education about the risk factors and cancer prevention helps in early lung cancer detection.

Background: Triple-negative breast cancer (TNBC) is a heterogeneous, recurring cancer characterized by a high rate of metastasis, poor prognosis, and lack of efficient therapies. KBU2046, a small molecule inhibitor, can inhibit cell motility in malignant tumors, including breast cancer. However, the specific targets and the corresponding mechanism of its function remain unclear.

Methods: In this study, we employed (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium) (MTS) assay and transwell assay to investigate the impact of KBU2046 on the proliferation and migration of TNBC cells in vitro. RNA-Seq was used to explore the targets of KBU2046 that inhibit the motility of TNBC. Finally, confirmed the predicted important signaling pathways through RT-qPCR and western blotting.

Results: In this study, we found that KBU2046 functioned as a novel transforming growth factor-β (TGF-β1) inhibitor, effectively suppressing tumor cell motility in vitro. Mechanistically, it directly down-regulated leucine-rich repeat-containing 8 family, member E (LRRC8E), latent TGFβ-binding protein 3 (LTBP3), dynein light chain 1 (DNAL1), and MAF family of bZIP transcription factors (MAFF) genes, along with reduced protein expression of the integrin family. Additionally, KBU2046 decreased phosphorylation levels of Raf and ERK. This deactivation of the ERK signaling pathway impeded cancer invasion and metastasis.

Conclusions: In summary, these findings advocate for the utilization of TGF-β1 as a diagnostic and prognostic biomarker and as a therapeutic target in TNBC. Furthermore, our data underscore the potential of KBU2046 as a novel therapeutic strategy for combating cancer metastasis.