Cancer Biology & Therapy最新文献

Background: Conventional treatments for bladder cancer exhibit various limitations. Therefore, natural products, such as jujuboside A (JuA), have been explored for their multi-target effects and low toxicity. However, the specific effects of JuA in bladder cancer remain unclear.

Objective: To determine whether JuA affects mitochondrial energy metabolism and apoptosis in bladder cancer cells by regulating the ATPase Na+/K+ transporting subunit alpha 2 (ATP1A2) expression.

Methods: Differentially expressed genes (DEGs) in bladder cancer were analyzed using the GSE133624 dataset. ATP1A2 overexpression and knockdown bladder cancer cell models were constructed. Cell phenotypes and markers related to apoptosis and mitochondrial energy metabolism were assessed. Moreover, targeting effects of JuA were investigated.

Results: Interleukin (IL)-6, ATP1A2, and hydroxysteroid 11-beta dehydrogenase 1 were identified as potential JuA targets, with ATP1A2 being the main target. ATP1A2 overexpression enhanced the viability and inhibited the apoptosis of bladder cancer cells and promoted mitochondrial energy metabolism in vitro, whereas ATP1A2 knockdown had the opposite effects. JuA decreased cell viability, inhibited ATP1A2 expression, and disrupted mitochondrial energy metabolism. These anticancer effects of JuA were reversed by ATP1A2 overexpression.

Conclusion: This study elucidated the molecular mechanism by which JuA regulates mitochondrial energy metabolism and induces apoptosis in bladder cancer cells through targeted inhibition of ATP1A2. These findings reveal the crucial role of ATP1A2 in the energy metabolism and survival of bladder cancer cells, providing a new molecular perspective for a deeper understanding of the pathological mechanisms of bladder cancer.

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype with a poor prognosis and limited treatment options. Elevated Kinesin Family Member 14 (KIF14) expression in breast cancer (BC) is correlated with poor prognosis, but its role in TNBC remains unclear.

Methods: KIF14 expression was analyzed using TCGA, TIMER, and GEO databases, and its association with prognosis was assessed via Kaplan‒Meier plotter. Functional assays, including CCK-8, wound healing, and Transwell assays, were performed to evaluate KIF14's impact on TNBC cell proliferation, migration, and invasion. GO and KEGG analyses of transcriptome data were used to explore molecular mechanisms. The relationship between KIF14 expression and immune infiltration was assessed in the TIMER database. KIF14 expression in clinical samples was validated using qRT-PCR and immunohistochemistry, and its correlation with clinical features was examined.

Results: KIF14 was significantly upregulated in BC (P < 0.05), and elevated KIF14 expression was associated with poor prognosis. KIF14 knockdown reduced cell proliferation, migration, and invasion. Network analysis revealed its involvement in lipid metabolism, NF-κB, PI3K-AKT, and mTOR signaling pathways. Immune infiltration analysis showed a significant association between KIF14 and immune cell types.

Conclusion: KIF14 promotes TNBC progression and serves as a potential diagnostic and prognostic biomarker for TNBC.

Glioblastoma multiforme (GBM), the most invasive primary malignant tumor of the central nervous system, is characterized by an extremely poor prognosis and a high recurrence rate. Its significant molecular heterogeneity challenges precise diagnosis and treatment. Recently, with the rapid development of molecular pathology, the combination of histological and molecular typing has become the mainstream method for GBM diagnosis. Here, we review the impact of classic molecular markers on patient prognosis in GBM, as well as the different values of traditional and novel molecular markers in prognosis assessment. We initially discuss the correlation between molecular markers and recurrence, as well as the research progress of molecular markers in emerging technological fields. Moreover, we propose the challenges currently faced by molecular markers in glioblastoma and discuss future research directions in this field.

Objective: Aryl hydrocarbon receptor nuclear transporter-like 2 (ARNTL2) can bind to clock circadian regulator (CLOCK) to regulate gene expression and is abnormally expressed in various cancers. Nevertheless, its effects on esophageal cancer (ESCC) are unclear. This work can uncover the intriguing mechanism of ARNTL2 in ESCC.

Methods: Malignant phenotypes including cell proliferation, invasion, migration, and epithelial mesenchymal transition (EMT), were investigated. We established a BALB/c nude mouse (5-6 weeks) model with ESCC to verify the influence of ARNTL2/ANXA2/C-MYC axis. ESCC tissues (n = 100) and paired adjacent normal tissues (n = 100) from patients with ESCC were collected. The recruitment of ARNTL2 and CLOCK in ANXA2 promoter was studied by ChIP and dual-luciferase reporter assay. RIP and RNA pulldown were used to explore the relationship between ANXA2 and C-MYC mRNA.

Results: Compared to adjacent normal tissues, ESCC tissues developed the significant increase ARNTL2, ANXA2, and C-MYC. ARNTL2, which interacts with CLOCK, was recruited in ANXA2 promoter and elevated ANXA2. ARNTL2 silence reduced cell proliferation, migration and invasion and inhibited EMT, which was reversed by ANXA2 overexpression. ANXA2 can bind to the 3'UTR of C-MYC transcript; further assays confirmed that ANXA2 increased the protein abundance of C-MYC. ANXA2 knockdown resulted in a decrease in malignant phenotypes, whereas C-MYC overexpression reversed these changes. ARNTL2 silence inhibited the formation, growth and EMT of subcutaneous tumors and suppressed C-MYC; ANXA2 overexpression reversed these alterations.

Conclusion: ARNTL2 activated the transcription of ANXA2, which interacts with C-MYC transcript, promoting the development of malignant behaviors of ESCC cells.

Background: Aberrant N6-methyladenosine (m6A) modification is linked to cancer development and progression. However, the role of YTH N6-methyladenosine RNA binding protein F2 (YTHDF2), an m6A 'reader protein', in nasopharyngeal carcinoma (NPC) is poorly understood. This study aimed to clarify the role and mechanism of YTHDF2 in NPC development.

Methods: Bioinformatics analysis was performed to identify the differential expression, prognostic value, and enriched pathways of YTHDF2 in patients with NPC. Quantitative PCR, western blotting, and immunohistochemistry were used to detect mRNA and protein expression. Biological function of YTHDF2 was investigated using in vitro experiments, including proliferation, wound healing, and invasion assays. RNA immunoprecipitation sequencing (RIP-seq), RIP-qPCR, and Methylated RNA immunoprecipitation sequencing (MeRIP-seq) were employed to determine if YTHDF2 modulates forkhead box O1 (FOXO1) expression through m6A modification.

Results: YTHDF2 mRNA and protein levels were significantly increased in the NPC tissues and cell lines. Higher expression of YTHDF2 was associated with a poorer prognosis. Overexpressing YTHDF2 enhanced the NPC cell proliferation, migration, and invasion. Conversely, YTHDF2 knockdown inhibited these phenomena. Gene set enrichment analysis revealed that FOXO1-related signaling pathways were enriched in the YTHDF2-activated group. Mechanistically, YTHDF2 overexpression inhibited FOXO1 expression in NPC cells. RIP-seq, RIP-qPCR, and MeRIP-seq assays confirmed that YTHDF2 was bound to FOXO1 mRNA, reducing its stability and accelerated degradation.

Conclusion: YTHDF2 potentially functions as an oncogene in NPC by binding to the m6A site of FOXO1, reducing its expression, thereby promoting malignant behavior. It may also be a viable biomarker and therapeutic target for NPC.

Yes-associated protein 1 (YAP1) and its paralog TAZ serve as central mechanotransductive transcription coactivators that integrate mechanical cues from the extracellular matrix, such as stiffness and fluid shear stress, with epigenetic modifications to drive oncogenic processes. They regulate diverse biological functions, including proliferation, metastasis, immune evasion, autophagy, ferroptosis, and metabolism. This review highlights how YAP1/TAZ signaling is modulated by mechanosensitive pathways (Integrin/FAK, Rho GTPases) and epigenetic mechanisms (m6A methylation, DNA methylation), contributing to therapy resistance and disease progression. Targeting the mechano-epigenetic axis of YAP1/TAZ offers promising therapeutic strategies for cancer treatment.

Colorectal cancer is a heterogeneous and molecularly complex cancer that often leads to poor prognosis. The standard treatment includes surgical resection and adjuvant therapies such as chemotherapy, radiotherapy, targeted therapy, and immunotherapy. However, owing to the individual heterogeneity of patients, the effectiveness of these treatments is difficult to achieve consistently and efficiently. Patient-derived organoids (PDOs), by mimicking key genes, physical, and mechanical cues from the tumor microenvironment, simulates tumor heterogeneity, tissue structure, and molecular characteristics, as well as the cellular interactions within the tumor microenvironment. Additionally, it provides a more physiological and relevant environment for anticancer drug screening and predicting patient responses to personalized approaches, bridging the gap between simplified 2D models and animal models. Here, we review the roles of PDOs in customizing CRC treatment, discussing its roles in predicting drug sensitivity, drug screening, studying drug resistance mechanisms, simulating cell-to-cell interactions, and exploring immunotherapy targets to develop personalized therapies.

Background: Multiple myeloma (MM) features plasma cell (PC) heterogeneity and alterations in B-cell differentiation and immune regulation. Although lenalidomide/bortezomib/dexamethasone (RVd) and cyclophosphamide/bortezomib/dexamethasone (CyBorD) are clinically effective, their precise impacts on PC/B-cell maturation remain unclear.

Methods: We performed CyTOF profiling on bone marrow samples from RVd- (n = 47) and CyBorD-treated MM patients (n = 15), each compared to untreated cohort (n = 43). Within each therapeutic arm, responders (RVd, n = 35; CyBorD, n = 5) were compared to non-responders (RVd, n = 12; CyBorD, n = 10).

Results: RVd and CyBorD therapies exerted distinct immune modulation patterns, differentially affecting PC, early B-cell stages, and naive T cells. Evaluation of transcriptional B-cell regulators in B-cell lymphopoiesis revealed that both regimens decreased IRF4, CXCR4, and FGFR3 while upregulating Pax-5 across B-cell stages and PC. RVd uniquely upregulated MYD88 and c-Myc and decreased sXBP1; its responders further suppressed BLIMP-1 and FGFR3. In contrast, CyBorD elevated sXBP1, BLIMP-1, and Notch-1 while reducing c-Myc in the B and PC subsets. Both therapies increased the expression of the stemness factor KLF4 and variably modulated NANOG; CyBorD altered Nestin and RARα2 in responder PCs, whereas RVd suppressed OCT3/4. Shared immunophenotypic aberrations included decreased MMSET, CD200, and CD52, and increased CD47, CD81, and CD44 in B-cell compartments. In PC, both regimens elevated CD338 while reducing CD47, CD319, and CD138. RVd responders further downregulated CD56, CD269, and CD329, and increased CD243.

Conclusions: These shared and divergent modulations elucidate the molecular underpinnings of RVd and CyBorD efficacy and inform precision regimen selection.

Background: Undifferentiated pleomorphic sarcoma (UPS) is a rare and aggressive soft tissue sarcoma with limited treatment options and a poor prognosis. As a complex karyotype tumor, UPS lacks recurrent targetable mutations, and response rates to standard first-line doxorubicin therapy are low. Phenotypic drug screening offers an alternative approach to identify new therapeutic targets without requiring prior knowledge of molecular mechanisms.

Methods: A library of FDA-approved compounds and a custom histone deacetylase (HDAC) inhibitor library were screened using well-annotated patient-derived cell lines. Hit compounds were further characterized using apoptosis assays and in vivo xenograft studies. Biomarkers of activity were evaluated using gene expression and western blot analyses. Synergy with doxorubicin was evaluated in combination assays.

Results: HDAC inhibitors emerged as a promising therapeutic class, demonstrating low IC₅₀ values across cell lines (14.8-26.89 nM), with quisinostat taken forward for further evaluation. Gene expression changes in EPAS1, FOXO1, AMOT, and FOSL1 were observed as potential biomarkers of activity. Combination assays revealed synergy between quisinostat and doxorubicin (average ZIP score: 1.02-15.65; ZIP_max: 3.98-33.71), increasing apoptotic cell death in vitro. In vivo, quisinostat alone and in combination with doxorubicin significantly reduced the tumor volume (vehicle 160.0 ± 63.2 mm³, doxorubicin 78.0 ± 35.2 mm³, quisinostat 84.3 ± 13.1 mm³, and combination 49.2 ± 10.2 mm³). Quisinostat also showed potent activity in leiomyosarcoma (LMS) cell lines (5.82-31.32 nM), which represent an additional complex karyotype soft tissue sarcoma.

Conclusions: Quisinostat demonstrated strong preclinical activity and synergy with standard-of-care doxorubicin in models of UPS and LMS.