American journal of cancer research最新文献

The mechanisms of metastasis and invasion in pancreatic cancer are promoted by the interaction between KRAS mutations and the transforming growth factor-β (TGF-β) pathway. However, the molecular mechanisms linking these pathways remain unclear. Downstream genes of KRAS pathway were identified by RNA sequencing in Panc-1 and MIA-PaCa2 cells. The function of the identified SOX8 was analyzed by using migration assays, western blotting of epithelial-mesenchymal transition (EMT) markers, and chemotherapy sensitivity. The correlation between SOX8 and TGF-β signaling was examined under recombinant TGF-β or TGF-β inhibitor treatment. SOX8 expression was also analyzed in resected specimens. SOX8 expression suppressed by KRAS knockdown, identifying it as a downstream regulated gene. SOX8 knockdown inhibited TGF-β signaling, reduced cell migration, altered EMT marker expression, and enhanced chemotherapy sensitivity. Furthermore, SOX8 knockdown activated the AKT/mTOR pathway, which was reversed by TGF-β inhibition. Clinically, high SOX8 expression correlated with poor prognosis. In conclusions, SOX8 functions as a molecular hub linking KRAS and TGF-β pathways, promoting epithelial-mesenchymal transition (EMT), invasive capacity, and chemotherapy resistance. This novel KRAS-SOX8-TGF-β axis plays the important role in invasion and metastasis of pancreatic cancer, suggesting SOX8 as a useful prognostic biomarker and therapeutic target.

This study examined the antitumor effects and molecular mechanisms of isorhamnetin in glioma treatment with a particular focus on its regulation of the PI3K/Akt signaling pathway, for developing targeted therapies. Using network pharmacology, we identified isorhamnetin could be used as a potential active ingredient in the regulation of glioblastoma (GBM) through the PI3K/Akt pathway. Bibliometric analysis was then used to review the current state and the developing trends in isorhamnetin research for anti-tumor applications. It was confirmed that isorhamnetin exerts its effects via the PI3K/Akt pathway. Our in vitro experiments showed further that isorhamnetin inhibits the proliferation and migration of glioma cells in a dose-dependent manner. Furthermore, isorhamnetin downregulated proteins related to the PI3K/Akt pathway, thereby suppressing its signaling activity. Isorhamnetin has antitumor effects against glioma by modulating the PI3K-Akt signaling pathway, providing experimental and mechanistic evidence for the potential use of isorhamnetin as a complementary GBM therapy.

Ubiquitin-conjugating enzyme E2W (UBE2W), a member of the ubiquitin-conjugating enzyme family, is highly expressed in pancreatic cancer (PC). However, the biological function of UBE2W in cancer, particularly in human PC, remains poorly understood. This study aimed to elucidate the molecular mechanism by which UBE2W regulates the initiation and progression of PC. Integrating multiple databases and validating with clinical samples, the study identified that UBE2W is significantly overexpressed in PC tissues. High UBE2W expression is closely associated with shortened overall survival, disease-specific survival, and disease-free survival in patients. In vitro and in vivo functional experiments demonstrated that UBE2W overexpression promotes the proliferation and migration of PC cells while inhibiting apoptosis. Conversely, UBE2W knockdown significantly reduces cell viability, induces apoptosis, and suppresses tumor growth in vivo. Mechanistically, UBE2W mediates K63-linked ubiquitination of p53, regulates p53 subcellular localization, and thereby impairs p53-mediated DNA damage repair and apoptotic pathways. Collectively, UBE2W inhibits the tumor-suppressive function of p53 and promotes PC progression through the aforementioned mechanism. Targeting the UBE2W-p53 axis provides a novel therapeutic strategy for PC, and the development of related inhibitors holds promise for improving patient prognosis.

Patients with advanced lung adenocarcinoma often develop metastasis and recurrence, leading to treatment failure. Anoikis resistance is a key step in tumor metastasis. Desmoglein-2 (DSG2) plays an important role in several cancers; however, its role in lung adenocarcinoma and its relationship to anoikis remain unclear. In this study, we aimed to investigate whether DSG2 regulates proliferation, invasion, and anoikis in lung adenocarcinoma cells and to explore the underlying mechanism. We analyzed DSG2 expression in lung cancer tissues and cells using online databases, examining the effects of DSG2 knockdown and overexpression on proliferation, invasion, and anoikis in lung adenocarcinoma cell models. Furthermore, we examined whether DSG2 functions through the integrin β1/focal adhesion kinase (FAK) signaling pathway and evaluated the effects of the integrin β1 agonist Pyrintegrin. DSG2 was highly expressed in lung adenocarcinoma tissues and cells and was associated with poor prognosis. DSG2 knockdown inhibited proliferation and invasion and promoted anoikis, whereas DSG2 overexpression increased invasion and proliferation and suppressed anoikis. Mechanistic analysis revealed that DSG2 activated the integrin β1/FAK signaling pathway. Pyrintegrin reversed the inhibitory effects of DSG2 knockdown on lung adenocarcinoma cells. DSG2 inhibits anoikis in lung adenocarcinoma cells by activating the integrin β1/FAK signaling pathway, thereby promoting cell proliferation and invasion.

CCT5, a subunit of the chaperonin-containing TCP1 complex, has been implicated in the development of various malignancies. However, its role in bladder cancer remains undefined. This study investigated the functional contribution of CCT5 and its association with Hippo/YAP signaling. Using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), CCT5 expression and its prognostic significance were analyzed. Single-cell and spatial transcriptomics were employed to explore expression patterns and cellular heterogeneity. Functional assessments were conducted in vitro and in vivo using xenografts. To elucidate the underlying mechanisms, RNA-seq was integrated with Western blotting analysis. CCT5 was found to be upregulated in bladder cancer and correlated with poor prognosis and aggressive pathological features. Single-cell and spatial analyses revealed that CCT5 was enriched in malignant epithelial subpopulations with high CNV scores, activated oncogenic pathways, and extensive cell-cell interactions. Functionally, CCT5 promoted proliferation, migration, invasion, and G1/S transition while inhibiting apoptosis; its depletion reduced xenograft growth. At the signaling level, CCT5 knockdown enhanced phosphorylation of MST1, LATS1, and YAP, without significant changes in total protein levels, suggesting activation of Hippo/YAP signaling. These findings highlight CCT5 as an oncogenic factor in bladder cancer, potentially acting through the regulation of Hippo/YAP signaling, and propose its potential as a biomarker and therapeutic target in bladder cancer.

This retrospective study evaluated the prognostic significance of pretreatment maximum standardized uptake value of the primary tumor (SUV-T) and the metastatic lymph nodes (SUV-N) in 146 patients with lymph node-positive hypopharyngeal squamous cell carcinoma (HPSCC) treated with definitive chemoradiotherapy between 2005 and 2013. Pretreatment ¹⁸F-FDG PET/CT was utilized to calculate the SUV-T and SUV-N, with clinical correlations assessed via Gamma statistic and survival outcomes analyzed using Kaplan-Meier methods and multivariable Cox regression. The results were further strengthened using multivariable Fine-Gray competing risk regression analysis, considering death as a competing risk when appropriate. After a median follow-up of 9.0 years (95% CI: 7.7-10.2), SUV-N correlated significantly with N category (Gamma coefficient = 0.63, P < 0.001), AJCC stage (Gamma coefficient = 0.53, P = 0.005), and radiologic extranodal extension (Gamma coefficient = 0.80, P < 0.001). SUV-N ≥ 13 predicted worse 5-year regional control (51.8% vs 86.1%, P < 0.001) and showed a borderline significant association with overall survival (26.3% vs 42.6%, P = 0.074). Multivariable analysis confirmed SUV-N ≥ 13 as an independent predictor of regional progression (HR = 4.59, P < 0.001). Competing risk analysis further confirmed that SUV-N ≥ 13 remained a robust predictor of regional progression (subdistribution hazard ratio [SHR] = 4.65; 95% CI: 2.23-9.69; P < 0.001), even after accounting for death as a competing risk. Conversely, radiotherapy dose escalation to 72-74 Gy (EQD2) significantly reduced the risk of regional progression (multivariable Cox regression: HR = 0.41, P = 0.047; multivariable competing risk regression: SHR = 0.37; 95% CI: 0.17-0.84; P = 0.017). Exploratory subgroup analysis revealed that this therapeutic benefit was primarily driven by the high SUV-N subgroup (SUV-N ≥ 13), where dose escalation significantly reduced regional progression (Fine-Gray P = 0.018), whereas no such benefit was observed in the low SUV-N subgroup (Fine-Gray P = 0.740). In contrast, SUV-T was not prognostic for survival outcomes. In conclusion, high pretreatment SUV-N is an independent prognostic factor for regional progression in node-positive HPSCC undergoing definitive chemoradiotherapy. Integrating SUV-N into treatment planning may guide intensified therapies for high-risk patients.

This study investigated the role of anlotinib in restoring osimertinib sensitivity in EGFR-mutant non-small cell lung cancer (NSCLC) by targeting the Wnt/β-catenin/YAP signaling and PD-L1 expression. Using osimertinib-resistant HCC827 cells with high PD-L1 expression, a stable PD-L1 knockdown line (Sh-PD-L1) was generated through lentiviral vectors. Resistance was induced by stepwise exposure to osimertinib, and the two constructed resistant cell lines were named OR (osimertinib-resistant) and Sh-PD-L1-OR (PD-L1 knockdown osimertinib-resistant) cell lines. Functional assays, including wound healing, Transwell, and MTT, along with Western blot analysis, were conducted in both cell and animal models. Sh-PD-L1 significantly reduced PD-L1 and EGFR expression (P < 0.001), decreased cell viability, and lowered IC50 values compared to parental cells (P < 0.001). In OR, PD-L1 expression was elevated, and PD-L1 knockdown in the Sh-PD-L1-OR group reduced both PD-L1 and EGFR levels (P < 0.001), enhanced YAP inhibition, and reversed Wnt/β-catenin signaling activation (P < 0.05). Anlotinib treatment reduced cell viability, migration, and invasion, with enhanced effects in the Sh-PD-L1-OR group (P < 0.001). It decreased p-EGFR, PD-L1, and YAP expression while activating GSK3β and reducing β-catenin phosphorylation (P < 0.05). In vivo, anlotinib reduced tumor growth in Sh-PD-L1-OR models (P < 0.01), with decreased expression of EGFR, PD-L1, YAP, and β-catenin. These findings suggest that high PD-L1 expression promotes osimertinib resistance through activation of YAP and Wnt/β-catenin, and that anlotinib combined with osimertinib can reverse resistance by restoring GSK3β activity, activating the Hippo pathway, and inhibiting β-catenin signaling.

Helicobacter pylori (H. pylori) infection is a major risk factor for gastric cancer (GC). Although autophagy is involved in H. pylori infection, its role in H. pylori-associated tumorigenesis remains unclear. Here, we investigated whether enhancing autophagy suppresses GC malignancy under H. pylori infection. Autophagy and mitochondrial markers were analyzed in GC tissue microarrays and the TCGA-STAD dataset. Functional studies employed H. pylori (strain 49503)-infected GC cell lines and xenograft models, with autophagy manipulated by pharmacological induction, Atg5 knockout, gene silencing, or overexpression. Molecular and cellular analyses included Western blotting, luciferase reporter assays, RNA sequencing, transmission electron microscopy (TEM), mitochondrial function tests, and additional functional assays. We observed elevated levels of LC3 and p-Drp1 in tumor tissues. H. pylori infection increased autophagy, cell migration, sphere formation, and transient tumor growth, while reducing cell viability and colony formation; autophagy induction suppressed these malignant features. TEM revealed abundant autophagy-like vesicles and mitochondrial alterations in infected cells. Mechanistically, H. pylori activated the Erk1/2 and JNK signaling pathways to induce autophagy while inhibiting other oncogenic signaling pathways. Notably, although H. pylori induces robust autophagy, further enhancement of this process using autophagy inducers attenuated gastric cancer malignancy, suggesting that further pharmacological modulation of autophagy warrants evaluation as a potential therapeutic strategy.

This study developed an attention-based multi-instance deep convolutional neural network (CRPNet) for the early prediction of postoperative recurrence in clear cell renal cell carcinoma (ccRCC). The model was trained on 183 whole slide images (WSIs) from ccRCC patients and validated on an internal cohort of 75 WSIs. Its prognostic performance was evaluated using Kaplan-Meier analysis, AUC, accuracy, precision, recall, false positive/negative rates (FPR/FNR), C-index, and hazard ratio (HR), and was compared against established tools including the UISS, SSIGN, and Karakiewicz nomograms. Results demonstrated that CRPNet-stratified high-risk groups had significantly poorer prognosis in both training and validation sets (P < 0.001), with consistency across subgroups based on T-stage, WHO/ISUP grade, and necrosis. In the training cohort, CRPNet achieved an AUC of 0.994 (95% CI: 0.974-1.000), accuracy of 97.70%, precision/recall of 95.56%, FPR of 1.55%, and FNR of 4.45%. In the validation cohort, it maintained an AUC of 0.879 (95% CI: 0.783-0.943), accuracy of 88.00%, precision of 85.71%, recall of 63.16%, FPR of 0%, and FNR of 36.84%, outperforming all comparator models. CRPNet also yielded a superior C-index compared to clinical parameters and traditional nomograms, and exhibited the highest HR (12.078, 95% CI: 1.611-90.539). In conclusion, CRPNet surpasses conventional prognostic models in recurrence prediction accuracy, AUC, precision, C-index, and risk stratification, while demonstrating lower FPR and FNR, thereby offering improved prognostication for metastatic ccRCC.

Hepatocellular carcinoma (HCC) is one of the most malignant tumors worldwide. This study aimed to investigate the role of protein arginine methyltransferase 5 (PRMT5) in HCC. Gene expression was determined using reverse transcription-quantitative polymerase chain reaction, Western blot, and immunohistochemistry. The interaction between genes were determined using chromatin immunoprecipitation, glutathione-S-transferase pull-down, co-immunoprecipitation, and luciferase assays. m6A levels were determined using m6A dot assay. N6-methyladenosine (m6A) enrichment was determined using methylated RNA immunoprecipitation assay. Cellular functions were determined using Cell Counting Kit-8 assay and propidium iodide staining. Xenograft assay was conducted to further verify the role of PRMT5 in HCC. We found that overexpressed PRMT5 was upregulated in tumor protein p53 (TP53)-mutated HCC patients. TP53 epigenetically in activated PRMT5. PRMT5 deficiency promoted the ferroptosis of HCC cells in vitro and inhibited tumor growth in vivo. Moreover, PRMT5 could interact with RNA binding motif protein 15 (RBM15) to activate ferritinophagy signaling. RBM15-mediated m6A modification of ferritin heavy chain 1 (FTH1), promoting its mRNA expression and stability. However, overexpression of FTH1 suppressed ferroptosis and promoted tumor growth. Taken together, PRMT5/RBM15/ferritinophagy signaling can be a potential target for HCC.