Molecular Carcinogenesis最新文献

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.

This study explored the effect of ubiquitin-specific protease 4 (USP4) on mitochondrial dynamics in esophageal squamous cell carcinoma (ESCC). USP4 and phosphoglycerate mutase 5 (PGAM5) expression in ESCC tissues was measured. ESCC cells were subjected to gain- and loss-of-function experiments, followed by examinations of proliferation, invasion, migration, apoptosis, light chain 3 (LC3), P62, Bcl2-associated X (Bax), B-cell lymphoma 2 (Bcl2), Cytochrome c (CytC), caspase3, mitochondrial membrane potential (MMP), mitochondrial reactive oxygen species (mtROS), and ROS. An in vivo tumor formation model of ESCC was established for in vivo verification. The relationship between USP4 and PGAM5 was analyzed. USP4 and PGAM5 expression was high in ESCC tissues. Mechanistically, USP4 eliminated K48-linked ubiquitin chains to maintain PGAM5 stability. PGAM5 knockdown impaired malignant behaviors of ESCC cells, reduced LC-3I-to-LC-3II conversion, increased mtROS, ROS, and P62 levels, activated the caspase-dependent mitochondrial pathway, and decreased MMP. Overexpressing USP4 increased MMP and Bcl2 expression while lowering Bax, CytoC, cleaved caspase3, and mtROS levels in ESCC cells, which was nullified by PGAM5 knockdown. Ectopic USP4 accelerated tumor growth in mice, which was reversed by PGAM5 knockdown. Collectively, USP4 promotes cell growth and excessive mitophagy in ESCC by stabilizing PGAM5.

Alternative splicing of FOXM1 produces different isoforms, which have been proven to exist and have complex functions. One of the isoforms of FOXM1, isoform ENST00000535350, is a short noncoding RNA sequence, designated as FOXM1s here. We determined the function and mechanism of FOXM1s-encoded peptide, FOXM1s, in the development and progression of pancreatic cancer. The expression of FOXM1s as noncoding RNA in pancreatic cancer tissues and cell lines was analyzed by RT-PCR. Gene expression and its association with clinicopathologic characteristics of patients with PDAC were analyzed using IF and bioinformatics. The effects on cell proliferation, migration, invasion, tumor stemness, and on PI3K/AKT signaling were evaluated through in vitro biology methods and functionally validated in mouse models by using overexpression and knockdown approaches. The expression of FOXM1s in human pancreatic cancer tissues and cell lines was significantly increased. The overexpression of FOXM1s had a promoting effect on pancreatic cancer, while the mutation of FOXM1s attenuated its effect, indicating that FOXM1s exerted its role potentially through ORF2-encoded a peptide. The specific antibody #FOXM1s was used to validate that FOXM1s expressed a predicted peptide, FOXM1s, and its expression was upregulated in pancreatic cancer. FOXM1s significantly promoted the proliferation, migration, and invasion of pancreatic cancer cells, facilitated liver metastasis, and upregulated the expression of stem-related genes in pancreatic cancer. Mechanistically, the FOXM1s peptide encoded by FOXM1s activated the PI3K/AKT signaling pathway. FOXM1s encodes a FOXM1s peptide and exhibits oncogenic function in the pancreatic cancer development progression at least in part through activating PI3K/AKT signaling pathway. This novel molecule could serve as a potential therapeutic target.

The solute carrier protein SLC5A6 is associated with multiple malignant tumors, while its role in cervical cancer (CC) remains unexplored. This study aimed to investigate the expression pattern, biological functions, and underlying mechanisms of SLC5A6 in cervical cancer. It was found that the expression of SLC5A6 was significantly upregulated in cervical cancer tissues, and its high expression was associated with poorer overall survival of patients. In vitro functional experiments conducted in HeLa and SiHa cell lines demonstrated that overexpression of SLC5A6 enhanced cell proliferation, colony formation, and migration abilities, while inhibiting cell apoptosis; conversely, knockdown of SLC5A6 suppressed these oncogenic phenotypes. Further in vivo experiments confirmed that knockdown of SLC5A6 could inhibit the growth of xenograft tumors. Through transcriptomic analysis and pathway enrichment analysis, this study identified lipid metabolism as a key downstream pathway of SLC5A6, in which fatty acid synthase (FASN) serves as a crucial effector molecule. Mechanistically, SLC5A6 is responsible for the transmembrane transport of biotin. Reduced expression of SLC5A6 leads to a decrease in the expression of biotin-dependent acetyl-CoA carboxylase (ACC), which in turn downregulates its downstream target gene FASN. Importantly, knockdown of FASN could reverse the promotional effect of SLC5A6 overexpression on the growth of cervical cancer cells, indicating that SLC5A6 promotes cervical cancer progression through FASN-mediated reprogramming of lipid metabolism. In conclusion, this study identified SLC5A6 as a novel oncogenic factor in cervical cancer and reveals its mechanism of regulating lipid metabolism via FASN, suggesting that targeting the SLC5A6-FASN axis may serve as a potential therapeutic strategy for cervical cancer.

Cancer stem cells (CSCs) are characterized by various properties such as hyperactive Wnt pathway, increased chemoresistance, angiogenesis, autophagy, EMT and decreased apoptotic activity. SFRP4 micropeptides, SC-301 and SC-401 derived from cysteine rich domain (CRD) and netrin like domain (NLD) domains respectively have shown to exhibit significant anti-CSC properties. In this study, based on our preliminary investigation, which showed that miR-203a was downregulated in ovarian CSCs and was subsequently activated by treatment with SFRP4 micropeptides, we investigated whether miR-203a plays any part in SFRP4 micropeptide-mediated ovarian CSC inhibition in PA-1 and SKOV-3 cell lines. SFRP4 micropeptide-treated and miR-203a mimic-overexpressing ovarian CSCs were subjected to various assays, and the results showed that miR-203a overexpression by the SFRP4 micropeptide treatment resulted in disruption of sphere-forming capacity and induction of caspase activity in ovarian CSCs. Furthermore, miR-203a expression upon micropeptide treatment resulted in the increased levels of E-cad and decreased levels of N-cad, Snail and Twist, indicating reversal of EMT along with the significant reduction in migratory potential of ovarian CSCs. Our findings for the first time indicated the possible role of miR-203a in regulating autophagy in ovarian CSCs, and reactivation of miR-203a by SFRP4 micropeptides was sufficient to halt the autophagic machinery in ovarian CSCs.

Chemotherapy remains the frontline treatment strategy for triple-negative breast cancer (TNBC). However, the aggressive nature of TNBC, due to metabolic reprogramming, is often associated with chemoresistance, which limits treatment efficacy. Herein, we investigated the impact of altered lipid homeostasis, in particular, the fatty acid β-oxidation (FAO) pathway, during doxorubicin (Dox)-induced chemoresistance and its effect on drug retention and efficacy in TNBC cells. Results indicate that Dox-induced chemoresistance in MDA-MB-231 cells and an in vivo Dox-resistance breast cancer model in SCID mice are associated with a marked upregulation of FAO. Intriguingly, the basal levels of carnitine palmitoyltransferase 1 (CPT1; a rate-limiting enzyme of FAO), CD36, (a fatty acid translocase), FAO-related gene transcript levels, and acetyl-CoA production were significantly elevated with increased degree of Dox resistance. These changes were paralleled by enhanced uptake of fatty acids and their oxidation. Dox-resistance in TNBC cells was associated with enhanced mitochondrial respiration, possibly due to increased activities of complex I and IV. Conversely, inhibition of CPT1 by etomoxir caused increased intracellular Dox retention, leading to Dox-induced cytotoxicity and attenuating the invasiveness of TNBC cells. Importantly, FAO-derived ATP levels, compared to glucose-derived ATP, seem to enhance the invasiveness of Dox-resistant cells. Mechanistically, Dox-resistance potentiated FAO via CREB activation, which in turn led to the enhancement of the PGC1α/PPARα/CD36-CPT1 axis. Taken together, Dox-resistance reprograms cellular metabolism towards FAO regulatory circuit sustaining the mitochondrial bioenergetics, promoting drug efflux, and accentuating breast cancer progression. Based on these findings, it is possible that FAO inhibitors effectively combat drug-induced TNBC chemoresistance.

The m⁵C RNA modifications have been implicated in the pathogenesis of urothelial carcinoma and hold potential as prognostic biomarkers for muscle-invasive bladder cancer (MIBC) patients. In this study, we developed an MIBC-risk model by integrating m⁵C modification-related genes and differentially expressed genes using Nanopore sequencing and a machine learning approach. Compared to our previous research, we observed that m⁵C modifications are more functional, with the most enriched regions being the 3'UTR and exons. Our analysis revealed differential m⁵C methylation sites in several well-characterized cancer-related genes, including BMI1, PTEN, MALAT1, FADD, STAT5A, BIRC6, FOXO3, CCNG1, PAK2, UBE2L3, SMARCB1, and TUG1. Functional enrichment analysis demonstrated significant involvement of these genes in key oncogenic pathways, particularly DNA damage response, double-strand break repair, p53 signaling, MAPK cascade, NF-κB signaling, and cell proliferation/migration pathways. Unlike models based on single factors, the combination of m⁵C modification-related genes and differentially expressed genes resulted in a more effective classification model. This approach yielded an optimized 11-gene prognostic signature comprising GGA1, NUMBL, ECHDC2, NLRC5, EIF2D, GJA1, XPC, DAZAP2, C6orf120, WDR45, and CES1, which demonstrated superior predictive performance in TCGA MIBC patients. These findings establish m⁵C RNA modification patterns as promising molecular signatures for MIBC prognosis and potential therapeutic targets.

Triple-negative breast cancer (TNBC) is a particularly aggressive malignant tumor. Pachymic acid (PA), a bioactive triterpenoid, has demonstrated multi-target therapeutic effects in TNBC. However, the detailed molecular networks responsible for its anti-TNBC effects have not yet been fully elucidated. The therapeutic potential of PA was evaluated by measuring cell viability, proliferation, invasion, and migration. The impact on ferroptosis was assessed by detecting ROS, MDA, GSH, and Fe2⁺ levels. Animal xenograft experiments were used to analyze the role in vivo. Expression analysis was performed using immunoblot, quantitative PCR, and immunohistochemical assays. PA exhibited antiproliferative, anti-migratory, and anti-invasive effects on BT-549 and MDA-MB-231 cells in vitro. PA induced oxidative stress and triggered ferroptosis in BT-549 and MDA-MB-231 cells. Kinesin family member 18B (KIF18B) was overexpressed in TNBC and was reduced by PA treatment. KIF18B restoration counteracted PA-mediated antiproliferative, anti-migratory, anti-invasive, and pro-ferroptosis effects on BT-549 and MDA-MB-231 cells. Furthermore, restored expression of KIF18B attenuated the efficacy of PA in reducing xenograft growth in vivo. Our study demonstrates that PA suppresses TNBC progression by inducing ferroptosis and inhibiting malignant phenotypes through KIF18B downregulation, offering experimental evidence supporting the clinical potential of PA as a novel therapeutic agent for TNBC treatment.