Molecular Carcinogenesis最新文献

Ewing sarcoma (ES) is an aggressive bone malignancy with poor outcomes for chemotherapy-resistant patients, yet the mechanisms underlying vincristine resistance remain unclear. Here, we identify protein kinase inhibitor alpha (PKIA) as a critical driver of chemoresistance through cAMP-EPAC signaling reprogramming. Transcriptomic analysis of vincristine-resistant ES cells revealed PKIA upregulation, which correlated with poor survival in clinical cohorts (HR = 2.14, p < 0.001). Mechanistically, PKIA overexpression elevated intracellular cAMP levels but suppressed PKA activity, instead activating the noncanonical EPAC-Rap1-ERK pathway to promote drug efflux and survival. Pharmacological inhibition of EPAC with ESI-09 reversed resistance (IC~50~ reduction: 52%, p < 0.01), while PKIA knockdown restored vincristine sensitivity in xenografts. Strikingly, PKIA exhibited a dual role, with low expression in primary ES (potentially tumor-suppressive) and high expression in resistant/metastatic tumors (prosurvival), mirroring observations in prostate and hepatocellular cancers. Our work establishes PKIA as a therapeutic vulnerability and supports targeting the cAMP-EPAC axis to overcome chemoresistance in high-risk ES.

Colon cancer treatment remains a clinical challenge. Chaperonin containing TCP1 subunit 6 A (CCT6A) acts as an oncogene in multiple tumors. In this study, we investigated its roles in colon cancer cells. We analyzed CCT6A expression using single-cell datasets and the Gene Expression Profiling Interactive Analysis based on The Cancer Genome Atlas database. Immunohistochemistry, quantitative reverse transcription polymerase chain reaction, and western blot analysis were used to assess CCT6A expression levels in colon cancer tissues and cell lines. Additionally, specific roles of CCT6A in colon cancer was analyzed using cell counting kit-8, 5-ethynyl-2'-deoxyuridine staining, flow cytometry, wound healing, transwell, boron dipyrromethene staining, western blot analysis, and nude model mice. We found that CCT6A expression levels were significantly elevated in colon cancer tissues compared to those in normal tissues and predicted a worse prognosis. CCT6A induced proliferation, migration, invasion, epithelial-mesenchymal transition, and fatty acid synthesis and suppressed apoptosis in colon cancer cells. Mechanistically, CCT6A promoted colon cancer progression by increasing the cleavage of latency-associated peptide (LAP)-transforming growth factor-β1 (TGF-β1) to mature form of TGF-β and inducing Smad2/3 phosphorylation in colon cancer cells. Overall, CCT6A promoted colon cancer progression by modulating fatty acid metabolism and activating the TGF-β1/Smad signaling, serving as a potential therapeutic target for colon cancer.

Therapy acute myeloid leukemia (AML) is a heterogeneous malignant hematopoietic disease that arises either from an antecedent hematologic disorder, including myelodysplastic syndromes, myeloproliferative neoplasms, aplastic anemia, or as a result of exposure to genotoxic chemotherapeutic agents or radiotherapy (therapy-related AML). In this study, we describe a case of therapy AML after treatment for breast, uterine, and rectal malignancies in a patient with a special fusion gene-RUNX1::HMGN1.

Chemotherapy continues to be the standard of care for metastatic malignancies, such as triple-negative breast cancer (TNBC). Although the treatment strategy increases survival rates marginally, it frequently leads to the development of resistant disease and side effects. It is imperative to develop an alternate chemotherapy formulation with better efficacy and lesser adverse effects in TNBC patients. Cell viability and cholesterol level were measured using spectrophotometer and fluorometric assays. The 4T1 syngeneic BALB/c female mice were used as an in vivo metastatic TNBC model. Simvastatin (Sim) and Metformin (Met) were administered in combination (3.5-7.0 and 175-350 μg/g body weight, respectively) and alone (Sim 7.0 μg/g/day, or Met 350 μg/g/day) orally over an 8-week period, and the standard Anticancer drug docetaxel (Doc) was administered at a dose of 24 μg/g body weight through IP injection every 3 weeks. Phosphorylation levels of protein and histopathology of tumors were studied by immunoblot and H & E staining methods, respectively. We report that the viability of TNBC cells is significantly and synergistically reduced by Sim and Met co-treatment, with negligible adverse effects on normal breast cell line. Sim Met combination down regulates phosphorylation at specific sites of AKT (Ser-473/Thr-308) and AMPKα (Ser-485/491) and up regulates ACC phosphorylation (Ser-79), which in turn minimizes the cellular cholesterol synthesis in the TNBC model. Further study demonstrated that the combination significantly reduced tumor formation effectively than docetaxel. Study confirmed that the combination of Sim and Met is a promising chemotherapeutic approach for metastatic TNBC.

Metastasis remains the primary determinant of poor prognosis in nasopharyngeal carcinoma (NPC). While dysregulated ubiquitination drives cancer progression, the functional contributions of deubiquitinating enzymes (DUBs) to NPC dissemination are poorly defined. Here, we investigated USP2, a DUB implicated in oncogenesis, as a potential regulator of NPC migration and invasion. In our study, bioinformatics analysis of the GEO data set GSE200792 identified USP2 as a metastasis-associated gene with elevated m⁶A methylation and mRNA levels in metastatic NPC. Validation employed qPCR, Western blot, and immunohistochemistry in clinical samples and NPC cell lines. Functional assays included CCK-8, flow cytometry, Transwell, wound healing, and mechanistic studies such as cyclohexane chase, co-immunoprecipitation, ubiquitination assays were performed under USP2 knockdown/overexpression and NF-κB inhibition. Our results showed that USP2 was significantly upregulated in metastatic NPC tissues and cell lines. USP2 knockdown suppressed proliferation, migration, and invasion, induced apoptosis, and attenuated NF-κB activation by reducing nuclear p65 and TRAF2/MMP2 expression. Conversely, USP2 overexpression enhanced malignancy, which was reversed by NF-κB inhibition. Critically, USP2 directly bound MMP2, extended its protein half-life, and reduced K48-linked polyubiquitination. In conclusion, USP2 drives NPC migration and invasion by activating TRAF2-dependent NF-κB signaling and directly mediating K48-linked deubiquitination of MMP2, dually enhancing MMP2 expression. Targeting the USP2-MMP2 axis may offer a novel therapeutic strategy to impede NPC dissemination, addressing an unmet clinical need in advanced disease.

Prostate cancer (PCa) is one of the most common genitourinary malignancies in men worldwide. As a 5-methylcytosine (m5C) methyltransferase, NSUN2 has been implicated in regulating PCa progression. This study aimed to investigate the role of NSUN2 in PCa and elucidate its underlying mechanisms. The biological behaviors of PCa cells were assessed using Cell Counting Kit-8, EdU incorporation, and Transwell assays. The expression levels of relevant RNAs were determined via quantitative real-time PCR. The interaction between NSUN2 and YES proto-oncogene 1 (YES1) was examined through methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), and dual-luciferase reporter assays. Results showed that NSUN2 was elevated in PCa, and its downregulation suppressed cell viability, proliferation, migration, and invasion. Mechanistically, NSUN2 interacted with YES1 and stabilized its mRNA by promoting m5C modification on YES1. The oncogenic role of NSUN2 was further confirmed in xenograft models in vivo. In conclusion, our study demonstrated that NSUN2 facilitated malignant proliferation and migration of PCa cells by enhancing YES1 mRNA stability via m5C modification. These findings suggested that both NSUN2 and YES1 may serve as potential therapeutic targets for PCa, offering new strategies for treatment.

M2-like tumor-associated macrophages (TAMs) exert immunosuppressive and protumorigenic functions in hepatocellular carcinoma (HCC). In this study, we explored the function and mechanism of Type IIA topoisomerase (TOP2A) in TAM recruitment and M2 polarization in the HCC microenvironment. The IGF2BP3-TOP2A relationship was confirmed by RIP, MeRIP, luciferase, and mRNA stability assays. Coculture experiments using a transwell system were performed to analyze the impact on the migration, CD206⁺ cell population, and M2-related marker expression in THP-1-differentiated macrophages (THP-1-M0). Xenograft models were constructed to evaluate TOP2A's role in tumor growth. Expression analysis was performed by quantitative PCR (qPCR), immunoblotting, and immunohistochemical staining. Increased TOP2A expression was associated with advanced tumor stage and worse outcomes in HCC. IGF2BP3 was upregulated and positively correlated with TOP2A expression in HCC samples. TOP2A depletion reduced THP-1-M0 migration and M2 polarization in vitro and attenuated xenograft growth by suppressing TAM infiltration and M2 polarization in vivo. Mechanistically, IGF2BP3 recognized METTL3-catalyzed m6A sites to increase the stability and expression of TOP2A mRNA. TOP2A re-expression abolished IGF2BP3 knockdown-driven suppression of THP-1-M0 migration and M2 polarization. Moreover, TOP2A depletion decreased CCL2 production and YAP1 activation. CCL2 reconstruction or the Hippo pathway inhibitor XMU-MP-1 reversed TOP2A knockdown-driven suppression of THP-1-M0 migration and M2 polarization. Our findings identify the IGF2BP3/TOP2A axis as a master regulator of TAM recruitment and polarization in HCC via IGF2BP3-m6A-dependent TOP2A stabilization to facilitate YAP1-mediated CCL2 upregulation, providing novel strategies to overcome immunosuppression and combat HCC.

Curcumin is a natural polyphenolic compound extracted from the rhizomes of Curcuma longa, exhibiting a wide range of biological activities, including anti-inflammatory, antioxidant, antitumor, antibacterial, antiviral, and neuroprotective effects. However, its low oral absorption rate and poor bioavailability limit its clinical application. To address this issue, this study synthesized a novel curcumin derivative, AN02, which significantly improves the absorption rate and bioavailability while enhancing its antitumor activity. This study focused on the antitumor mechanism of AN02 in ovarian cancer, particularly its ability to inhibit ovarian cancer cell proliferation, invasion, and migration by regulating the APC (Adenomatous Polyposis Coli)-SMAD4 (SMAD family member 4)-CTLA-4 (Cytotoxic T-Lymphocyte-Associated Protein 4) molecular axis. Experimental results demonstrated that AN02 significantly inhibited ovarian cancer cell proliferation at very low concentrations, with its half-maximal inhibitory concentration (IC₅₀) significantly lower than that of curcumin. Additionally, AN02 exerted its antitumor effects by activating the APC-SMAD4 molecular axis and inhibiting the CTLA-4 molecular axis. Silencing CTLA-4 inhibits the proliferation and immune escape of ovarian cancer. Further molecular mechanism studies revealed that APC directly regulates the SMAD4-CTLA-4 molecular axis, while SMAD4 forms a chaperone relationship with CTLA-4 and promotes CTLA-4 degradation through the K48-dependent ubiquitination pathway, thereby suppressing the malignant phenotype of ovarian cancer cells. These findings not only reveal the antitumor mechanism of AN02 but also provide new insights for the treatment of ovarian cancer. Animal experiments also demonstrated that AN02 significantly inhibits the proliferation of subcutaneous xenograft tumors in mice. As a novel curcumin derivative, AN02 exhibits significant antitumor activity and inhibits ovarian cancer progression by regulating the APC-SMAD4-CTLA-4 molecular axis. This study lays an important theoretical foundation for the development of novel antitumor drugs based on AN02, with significant clinical application potential. However, the long-term toxicity and safety of AN02 require further investigation to establish safe dosage standards for clinical use. Future studies will focus on exploring combination therapy strategies of AN02 in cisplatin-resistant ovarian cancer to provide new directions for precision treatment of ovarian cancer.

Metastasis is a major factor leading to an unfavorable prognosis in gastric cancer (GC). However, factors driving GC metastasis are not fully understood. Single-cell transcriptome analysis was done on three primary GC samples, one adjacent nontumor sample, and six GC metastasis samples (GSE163558) to clarify cellular composition characteristics, differential genes, and screen genes related to epithelial-mesenchymal transition (EMT). Effects of GPX3 on GC growth and metastasis were assessed through in vitro cell experiments, a GC liver metastasis model, a GC organoid model, and an organoid xenograft nude mouse model. The primary tumor samples showed a higher proportion of epithelial cells, and analysis revealed a significant reduction in GPX3 levels in GC metastasis samples within the subpopulation of epithelial cells undergoing EMT. Cell experiments demonstrated low expression of GPX3 in GC cells, and overexpression of GPX3 inhibited cell migration, invasion, and EMT in GC cells. Further validation in a nude mouse liver metastasis model confirmed the repressive role of GPX3 in GC metastasis. Additionally, GPX3 could inhibit the growth of patient-derived GC organoids and impede tumor growth and metastasis in an organoid xenograft nude mouse model. This study, based on single-cell transcriptome analysis, revealed the potential inhibitory factor GPX3 in metastatic GC and validated its effects on GC growth and metastasis using GC cells and organoids in vitro and in vivo experiments. These findings offer insights into understanding GC heterogeneity and targeting GPX3 in GC therapeutic strategies.

Hepatocellular carcinoma (HCC) constitutes approximately 90% of all liver cancer cases. Targeted drugs demonstrate significant potential in the treatment of advanced HCC; however, it is imperative to investigate novel and promising therapeutic targets to overcome the limitations of current targeted therapies. Zinc-finger MYM-type containing 4 (ZMYM4) has frequently been identified as a fusion gene, but the biological function of ZMYM4 in HCC is still unclear. In this study, we utilized The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to investigate the expression levels of ZMYM4 in HCC and to evaluate the correlation between ZMYM4 expression levels and both clinical characteristics and survival outcomes of HCC patients. Subsequently, clinical samples were utilized for further validation. Subsequently, the impact of ZMYM4 knockdown on the malignant progression of HCC cells was examined through a series of in vitro experiments. The specific regulatory relationship between miR-34a-5p and ZMYM4 was confirmed through a luciferase reporter assay. Ultimately, the regulatory effect of miR-34a-5p on ZMYM4 expression in HCC cells was examined. Bioinformatics analysis and clinical sample detection revealed that ZMYM4 expression was significantly upregulated in HCC and correlated with clinical stages and unfavorable prognosis in patients. When ZMYM4 expression was knocked down, the proliferation, migration, and invasion capabilities of HCC cells were significantly inhibited, while the apoptosis rate was markedly increased. Overexpression of ZMYM4 produced opposing effects. In HCC cells, miR-34a-5p directly targets ZMYM4. Upon overexpression of miR-34a-5p, the malignant phenotype of HCC cells was significantly inhibited. Notably, the overexpression of miR-34a-5p partially mitigated the promotional effect of ZMYM4 upregulation on the malignant progression of HCC cells. In conclusion, ZMYM4 is specifically targeted by miR-34a-5p in HCC and promotes the malignant progression of HCC. This suggests that ZMYM4 may serve as a potential biomarker for both the treatment and prognosis of HCC.