Cancer Biology & Therapy最新文献

KRAS mutations are common in non-small cell lung cancer (NSCLC) and are associated with patient prognosis; however, targeting KRAS has faced various difficulties. Currently, immunotherapy, chemotherapy, and chemoimmunotherapy play pivotal roles in the first-line treatment of KRAS-mutated NSCLC. Here, we summarize the current evidence on first-line therapies and compare the treatment outcomes and biomarkers for different regimens. KRAS inhibitors and other emerging alternative treatments are also discussed, as combining these drugs with immunotherapy may serve as a promising first-line treatment for KRAS-mutated NSCLC in the future. We hope that this review will assist in first-line treatment choices and shed light on the development of novel agents for KRAS-mutated NSCLC.

To explore the feasibility, safety, and effectiveness of brachytherapy of locally advanced bladder cancer, clinical data of 86 patients with locally advanced bladder cancer treated in the Department of Urology Surgery, Shanxi Provincial Cancer Hospital, between January 2015 and June 2019 were analyzed retrospectively. The patients were categorized into the study (n = 45) and control (n = 41) groups according to the treatment methods. Patients in the study group were treated with brachytherapy (intraoperative implantation of radioactive particles) + neoadjuvant chemotherapy (NAC), and those in the control group were treated with NAC. Patients in both groups underwent radical cystectomy (RC) + pelvic lymph node dissection. Postoperative pathological examinations proved that patients in both groups had urothelial carcinoma at stage pT₃-pT₄. The endpoints included 3-y locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), overall survival (OS), and adverse events after treatment. The efficacy and safety of interstitial implantation of radioactive particles for the treatment of locally advanced bladder cancer were assessed. The patients were followed up for 9-42 months. The 3-y LRFS was significantly higher in the study group (88.9%) than in the control group (60.9%) (p = .003). The 3-y DMFS in the study group (71.1%) and the control group (73.2%) was statistically similar (p = .945). The 3-y DFS and OS were not statistically significant between the two groups (DFS: study group 64.4% vs. control group 51.2%, p = .073; OS: study group 66.7% vs. control group 58.5%, p = .180). Local shifting of the particles was detected in three patients at 1 week to 1 month after the operations in the study group, but no related complications were observed. Blood events (anemia, leukocytopenia, and thrombocytopenia), liver and renal dysfunction, vomiting, diarrhea, and weakness were the major adverse reactions, which were alleviated after symptomatic treatments. The results have not statistically significant differences between the two groups in major adverse reactions. Compared to the NAC group, brachytherapy + NAC significantly prolongs the LRFS of patients with locally advanced urothelial bladder carcinoma who underwent RC + pelvic lymph node dissection. This surgery increases the LRFS, develops better personalized treatment plans, and improves treatment effectiveness. In addition, the treatment is safe and effective, with only limited adverse effects.

Sufficient MHC-I expression on cancer cells is essential for the recognition and killing of cancer cells by immune effector cytotoxic T-lymphocyte (CTL). An important mechanism of cancer immune escape is loss or down-regulation of MHC-I. This is frequently associated with reduced expression of NOD-like receptor (NLR) caspase recruitment domain containing protein 5 (NLRC5), genetically and epigenetically. NLRC5, a regulator of MHC-I, has been identified as a potential target of miR-4319 due to its complementary binding site for miR-4319, according to prediction by TargetScan (http://www.targetscan.org/). Inhibition of miR-4319 by IFN-γ (known as MHC-I increasing agent) to upregulate NLRC5 with upregulation of MHC-I in MHC-I-deficient breast cancer cells, however, remains unclear. After treatment with IFN-γ, miR-4319 was detected with qRT-PCR; NLRC5 protein was detected with western-blot; and MHC-I mRNA and protein were detected with qRT-PCR and western-blot, respectively. It was found statistically that miR-4319 was lower and NLRC5 protein was higher in groups of 50 U/ml and 100 U/ml IFN-γ, and MHC-I mRNA and protein were higher in all groups of different concentrations of IFN-γ, except for HLA-A protein in 25 U/ml IFN-γ group, with dose dependent tendency, compared with the control group. IFN-γ inhibits miR-4319 and upregulates NLRC5, thereby enhancing expression of MHC-I in SKBR3 breast cancer cells, while limitations include the absence of functional rescue experiments and in vivo validation. Along with direct cytotoxicity on tumor cells, IFN-γ's immunomodulatory effect strengthens tumor immunogenicity, counteracts immune evasion mechanisms, and potentially improves the efficacy of cancer immunotherapy.

Purpose: Metastatic castration-resistant prostate cancer (mCRPC) remains a significant therapeutic challenge and a leading cause of cancer-related mortality in men. PARP inhibitors like Olaparib are effective in homologous recombination repair (HRR)-deficient tumors, but resistance often arises through DNA repair restoration. This study explores the role of the structure-specific endonuclease subunit SLX1, a catalytic subunit of the SLX1-SLX4 endonuclease complex, in Olaparib resistance.

Methods: Data from The Cancer Genome Atlas (TCGA) were used for expression and survival analyses. The CRPC cell line DU145, which harbors BRCA1 and BRCA2 mutations, was used as a cell model for both in vitro and in vivo studies.

Results: Elevated SLX1A expression in prostate cancer tissues was associated with significantly reduced progression-free and overall survival. SLX1 protein was upregulated in androgen-resistant prostate cancer cell lines (DU145, 22RV1, PC3) and further increased in Olaparib-resistant DU145 (DU145-OR) cells. Silencing SLX1 via shRNA enhanced Olaparib sensitivity, reducing colony formation and increasing DNA damage and apoptosis in DU145 and DU145-OR cells. Mechanistically, SLX1 knockdown disrupted SLX4 interactions with critical DNA repair proteins (ERCC1-XPF, PLK1, and TOPBP1), impairing DNA repair complex stability. In vivo, SLX1-silenced DU145 xenografts treated with Olaparib showed significantly reduced tumor growth with decreased Ki-67 expression and increased apoptosis/necrosis compared to controls.

Conclusion: This study highlights SLX1 as both a prognostic marker and potential therapeutic target to enhance PARPi efficacy in advanced prostate cancer. Targeting SLX1 may be a promising strategy to overcome Olaparib resistance in mCRPC patients with homologous recombination deficiency.

Background: While NDUFAF6 is implicated in breast cancer, its specific role remains unclear.

Methods: The expression levels and prognostic significance of NDUFAF6 in breast cancer were assessed using The Cancer Genome Atlas, Gene Expression Omnibus, Kaplan-Meier plotter and cBio-Portal databases. We knocked down NDUFAF6 in breast cancer cells using small interfering RNA and investigated its effects on cell proliferation and migration ability. We performed gene expression analysis and validated key findings using protein analysis. We also assessed mitochondrial activity and cellular metabolism.

Results: NDUFAF6 was highly expressed in breast cancer, which was associated with a poorer prognosis. Knockdown of NDUFAF6 reduced the proliferation and migration ability of breast cancer cells. Transcriptome analysis revealed 2,101 differentially expressed genes enriched in apoptosis and mitochondrial signaling pathways. Western blot results showed NDUFAF6 knockdown enhanced apoptosis. In addition, differential gene enrichment analysis was related to mitochondrial signaling pathways, and western blot results verified that mitophagy was enhanced in NDUFAF6 knockdown breast cancer cells. JC-1 assay also showed that mitochondrial dysfunction and reactive oxygen species content were increased after knocking down NDUFAF6. In addition, basal and maximal mitochondrial oxygen consumption decreased, and intracellular glycogen content increased.

Conclusions: Knockdown of NDUFAF6 resulted in apoptosis and mitophagy in breast cancer cells and NDUFAF6 may be a potential molecular target for breast cancer therapy.

Our study aims to investigate the roles of embryonic lethal abnormal vision-like 1 (ELAVL1) and long non-coding RNA (LncRNA) NEAT1 in endometrial cancer (EC), focusing on their underlying molecular mechanisms.We obtained EC cell lines (HEC-1A, Ishikawa, RL95-2, HEC-1B, and AN3CA) from ATCC. We used siRNAs (si-ELAVL1#1 and si-ELAVL1#2) and overexpression RNAs (OE ELAVL1 and OE-NEAT1) for knockdown or overexpression of ELAVL1 and LncRNA NEAT1. We also employed 3-MA (5mM) or rapamycin (100µM) to inhibit or promote autophagy. Moreover, we conducted RNA immunoprecipitation (RIP) assays to confirm the interaction between LncRNA NEAT1 and ELAVL1. Cell Counting Kit-8 (CCK-8) and transwell assays were utilized to assess cell proliferation and migration. Additionally, we measured the expression of ELAVL1 and Beclin1 through Western blotting and RT-qPCR.ELAVL1 was found to be highly expressed in EC. Furthermore, ELAVL1 promoted the proliferation, invasion, and migration of EC cells through the regulation of Beclin1-related pathways. RIP assays revealed a direct interaction between LncRNA NEAT1 and ELAVL1, with ELAVL1 stabilizing LncRNA NEAT1 mRNA in EC cells. Additionally, we observed that ELAVL1 influenced EC cell proliferation, invasion, and migration through the regulation of LncRNA NEAT1-mediated regulation of Beclin1 expression. Moreover, in an animal study, we determined that ELAVL1 influenced endometrial cancer tumor growth through its interaction with LncRNA NEAT1, which mediated Beclin1 expression in vivo.In summary, our study showed that ELAVL1 regulated the malignant behavior of endometrial cancer cells through the modulation of LncRNA NEAT1-mediated regulation of Beclin1 expression.

Endoplasmic reticulum stress (ERS) has been implicated in the pathogenesis of various cancers, including colon cancer, by regulating tumor cell survival, growth, and immune response. However, the specific genes involved in ERS that could serve as prognostic markers in colon cancer remain underexplored. This study aims to identify and validate endoplasmic reticulum stress related genes (ERSRGs) in colon cancer that correlate with patient prognosis, thereby enhancing the understanding of ERS in oncological outcomes and potential therapeutic targeting. We utilized bioinformatics analyses to identify ERSRGs from publicly available colon cancer datasets. Differential expression analysis and survival analysis were performed to assess the prognostic significance of these genes. Validation was conducted through quantitative real-time PCR (RT-qPCR) on selected colon cancer cell lines. Our study identified nine ERS related genes (ASNS, ATF4, ATF6B, BOK, CLU, DDIT3, MANF, SLC39A14, TRAF2) involved in critical pathways including IL-12, PI3K-AKT, IL-7, and IL-23 signaling, and linked to 1-, 3-, and 5-year survival of patients with colon cancer. A multivariate Cox model based on these ERS related genes demonstrated significant prognostic power. Further, TRAF2 strong correlated with immune cells infiltration, suggesting its potential roles in modulating immune responses in the tumor microenvironment. The RT-qPCR validation confirmed the differential expression of these genes in human colon cancer cell lines versus human normal colonic epithelial cell line. The identified ERSRGs could serve as valuable prognostic markers and may offer new insights into the therapeutic targeting of ERS in colon cancer.

This study aimed to investigate the in vitro and in vivo antitumor effects and mechanisms of the small molecule anticancer drug CBL0137 in NK/T-cell lymphoma (NKTCL), as well as its efficacy when combined with chemotherapy or immunotherapy. Cell viability assays were performed to evaluate the inhibitory effect of CBL0137 on NKTCL cell proliferation in vitro. Flow cytometry was used to assess the effects of the drug on apoptosis and cell cycle progression. RNA sequencing (RNA-seq) was employed to explore the mechanism of action of CBL0137 in NKTCL, and Western blotting (WB) was used to validate the expression of related proteins. An in vivo xenograft model was used to confirm the antitumor activity of CBL0137. Additionally, immunohistochemistry analysis was conducted to further study tumor tissue. CBL0137 effectively inhibited the proliferation of NKTCL cells in vitro, induced apoptosis, and significantly blocked cell cycle progression. RNA-seq analysis revealed that CBL0137 exerts its antitumor effect primarily by interfering with DNA damage repair. In vivo experiments using xenografted mice confirmed the antitumor activity of CBL0137. CBL0137, when combined with PD-1 antibody, exhibits synergistic antitumor effects in mice, and its combination with cisplatin significantly enhances the sensitivity of NKTCL to cisplatin. CBL0137 inhibits DNA damage repair in NK/T-cell lymphoma and enhances its sensitivity to cisplatin.

Acute lymphocytic leukemia (ALL) is the most common leukemia in children, with the T-cell subtype (T-ALL) accounting for 15% of those cases. Despite advancements in the treatment of T-ALL, patients still face a dismal prognosis following their first relapse. Relapse can be attributed to the inability of chemotherapy agents to eradicate leukemia stem cells (LSC), which possess self-renewal capabilities and are responsible for the long-term maintenance of the disease. Mitochondria have been recognized as a therapeutic vulnerability for cancer stem cells, including LSCs. Mitocans have shown promise in T-ALL both in vitro and in vivo, with some currently in early-phase clinical trials. However, due to challenges in studying LSCs in T-ALL, our understanding of how mitochondrial function influences self-renewal remains limited. This review highlights the emerging literature on targeting mitochondria in diverse T-ALL models, emphasizing specific mitochondrial vulnerabilities linked to LSC self-renewal and their potential to significantly improve T-ALL treatment.