Cancer Cell International最新文献

Background: Ferroptosis is a therapeutic strategy for breast carcinoma (BC). Solasonine (SS) was linked to ferroptosis as a tumor suppressor. However, whether SS could treat BC by activating ferroptosis and its underlying mechanisms has not been reported.

Methods: We obtained the intersection of genes targeting SS and BC disease through network pharmacology. Bioinformatics analysis revealed that the intersection genes were primarily enriched in the extracellular signal-regulated kinase 2/mitogen-activated protein kinase (ERK2/MAPK) signaling pathway. The interaction modes of SS with ERK2 and epidermal growth factor receptor (EGFR) were simulated by molecular docking. We further detected the expressions of ERK2 and p-ERK2 in BC patients and the correlation between ERK2/p-ERK2 and ferroptosis. The effects and mechanism of SS on ferroptosis in BC were validated by mutation plasmids construction, immunohistology, wound healing, transwell assay, and western blotting using in vitro and in vivo models.

Results: ERK2 and p-ERK2 were up-regulated in BC patients, and the ERK2/p-ERK2 ratio was negatively correlated with ferroptosis. Molecular docking indicated that SS could bind to ERK2 and EGFR to inhibit the activity of the ERK2/MAPK pathway. In vitro and in vivo experiments confirmed that SS induced ferroptosis by inhibiting the ERK2/MAPK pathway, inhibiting proliferation, migration, and invasion of BC cells.

Conclusion: SS could inactivate the ERK2/MAPK pathway, thereby inducing ferroptosis and further inhibiting BC cell proliferation, migration, and invasion. This study clarified the potential mechanism of SS in BC and provided a theoretical basis for its clinical application.

Background: Bacillus Calmette-Guérin (BCG) is the primary method of postoperative perfusion treatment for bladder cancer. The myeloid cell leukemia gene-1 (Mcl-1) is closely associated with the development of malignant tumors. Previous research by our group has demonstrated that downregulating Mcl-1 using shRNA can enhance the efficacy of BCG treatment in bladder cancer. This study aims to investigate the impact of Mcl-1 downregulation in combination with BCG treatment on bladder cancer, macrophage polarization, and the underlying mechanism of action, with the goal of reducing recurrence and metastasis in bladder cancer.

Methods: The GSE190529 dataset was analyzed to identify differential genes for enrichment analysis. The WGCNA algorithm was then employed to pinpoint gene modules closely associated with the Mcl-1 gene. The overlapping genes between these modules and the differentially expressed genes were subjected to enrichment analysis in GO and KEGG pathways to unveil crucial signaling pathways. In vitro experiments involved the co-culture of Raw264.7 macrophages and MB49 to establish a tumor microenvironment model, while in vivo experiments utilized an MNU-induced rat bladder cancer model. Various methods including Enzyme-Linked Immunosorbent Assay (ELISA), Western blot, immunofluorescence, HE staining, etc. were utilized to assess macrophage polarization and the expression of proteins linked to the ASK1/MKK7/JNK/cJUN signaling pathway.

Results: Bioinformatics analysis indicates that the therapeutic mechanism of Mcl-1 in BCG treatment for bladder cancer may be linked to the Mitogen-Activated Protein Kinase (MAPK) signaling pathway. Both in vivo and in vitro experiments have demonstrated that the combination of BCG treatment and Mcl-1shRNA intervention results in elevated expression of M1 markers (TNF-α, CD86, INOS) and reduced expression of M2 markers (IL-10, CD206, Arg-1). Moreover, there was a notable increase in protein levels of P-ASK1, P-MKK7, P-JNK, P-cJUN, and CX43, leading to a significant rise in the apoptosis rate of bladder cancer cells and diminished proliferation, migration, and invasion capabilities. The expression of these markers can be reversed by employing the JNK signaling pathway inhibitor SP600125.

Conclusion: Down-regulation of Mcl-1 promotes the polarization of macrophages towards the M1 type through activation of the ASK1/MKK7/JNK signaling pathway. This enhances intercellular communication and improves the efficacy of BCG in bladder cancer treatment.

Gastrointestinal tumors remain the leading causes of cancer-related deaths, and their morbidity and mortality remain high, which imposes a great socio-economic burden globally. Mitochondrial homeostasis depend on proper function and interaction of mitochondrial biogenesis, mitochondrial dynamics (fission and fusion) and mitophagy. Recent studies have demonstrated close implication of mitochondrial homeostasis in gastrointestinal tumorigenesis and development. In this review, we summarized the research progress on gastrointestinal tumors and mitochondrial quality control, as well as the underlying molecular mechanisms. It is anticipated that the comprehensive understanding of mitochondrial homeostasis in gastrointestinal carcinogenesis would benefit the application of mitochondria-targeted therapies for gastrointestinal tumors in future.

Background: The persistent activation of the epidermal growth factor receptor (EGFR) leads to the activation of downstream oncogenic kinases and transcription factors, resulting in tumor progression and an increased resistance to cisplatin in bladder cancer (BC) cells. Lenvatinib, an oral multikinase inhibitor, has the potential to offer therapeutic benefits as an adjuvant treatment for BC patients. The investigation into its application in bladder cancer treatment is a valuable endeavor. The primary goal of this study is to confirm the effectiveness and mechanism of lenvatinib in inhibiting the progression of BC and enhancing the anticancer efficacy of cisplatin.

Materials: Three BC cell lines, namely, TSGH-8301, T24, and MB49, along with an MB49-bearing animal model, were utilized in this study.

Results: In vitro experiments utilizing MTT assays demonstrated that lenvatinib sensitized BC cells to cisplatin, exhibiting a synergistic effect. Flow cytometry indicated apoptotic events and signaling, presenting that lenvatinib effectively induced apoptosis and triggered extrinsic/intrinsic apoptotic pathways. In vivo studies using a mouse model of BC confirmed the antitumor efficacy of lenvatinib, demonstrating significant tumor growth suppression without inducing toxicity in normal tissues. Western blotting analysis and immunohistochemistry stain revealed EGF-phosphorylated EGFR and EGFR-mediated ERK/P38/NF-κB signaling were suppressed by treatment with lenvatinib. In addition, lenvatinib also suppressed anti-apoptotic (MCL1, c-FLIP, and XIAP) and metastasis-related factors (Twist, Snail-1, ZEB-1, ZEB-2, and MMP9) and promoted epithelial markers (E-cadherin) while reducing mesenchymal markers (N-cadherin).

Conclusion: In conclusion, the induction of apoptosis and the inhibition of EGFR/ERK/P38/NF-κB signaling are correlated with lenvatinib's ability to hinder tumor progression and enhance the cytotoxic effects of cisplatin in bladder cancer. These findings underscore the potential of lenvatinib as a therapeutic option for bladder cancer, either as a standalone treatment or in combination with cisplatin.

Background: Cervical cancer ranks as the fourth most common cancer among women, with cisplatin resistance posing a significant challenge to the long-term survival of patients.

Methods: The roles of NEK2 in cervical cancer were examined through bioinformatics analysis. Transfection efficiency and molecular mechanisms were assessed using real-time quantitative polymerase chain reaction (qRT-PCR) and western blotting (WB). To evaluate cell functions, a series of assays, including cell counting kit-8 (CCK-8), wound healing, transwell, colony formation, and flow cytometry (FCM), were performed on HeLa, SiHa, and HeLa/DDP (cisplatin-resistant) cell lines.

Results: We found that NEK2 is upregulated in cervical cancer tissues compared to normal tissues and is further elevated in cisplatin-resistant cervical cancer compared to cisplatin-sensitive cases. The overexpression of NEK2 is associated with enhanced cancer progression, poorer prognosis, and increased cisplatin resistance in cervical cancer patients. Notably, in the presence of cisplatin, the knockdown of NEK2 inhibited cell viability, proliferation, migration, invasion, and G2/M phase arrest in cervical cancer cells, while also enhancing the sensitivity of cisplatin-resistant cervical cancer cells through the inactivation of the Wnt/β-catenin signaling pathway.

Conclusions: NEK2 is upregulated in cervical squamous cell carcinoma (CESC) compared to normal tissues and exhibits higher levels in cisplatin-resistant CESC than in sensitive counterparts, correlating with disease progression and poor prognosis. Thus, NEK2 is implicated in the cisplatin resistance of CESC via the activation of the Wnt/β-catenin signaling pathway, suggesting its potential as a prognostic marker and a novel target for the diagnosis and treatment of cisplatin-resistant CESC.

Background and aim: Prostate cancer is the most common male malignancy. Current diagnostic methods using single TPSA and PHI lack specificity. Some researches have created nomograms for predicting risk, but these are not easily visualized. Our study aims to find the best negative predictive value (NPV) for PHI, then build a clustering model to display prostate cancer risk categories, particularly useful for patients with PSA > 20 and be actually applied in clinical work.

Method: We collected 708 patients in the training cohort and 143 in the validation cohort, divided into three groups based on their PSA levels. Next, we determined optimal and customized PHI cut-off values, calculated NPV and PPV, and selected logistic regression as the best method among several machine-learning algorithms. Subsequently, the significant variables were identified, and then a clustering algorithm was constructed. Finally, the model was validated and made available online for further clinical application.

Results: The Optimal PHI cut-off lower limits for PSA > 4, PSA4-20, PSA > 20 subgroups were 23.85, 24.35, and 40.75, with upper limits of 142.9, 143, and 135.6, respectively. The clustering model of the optimal cohort for PSA > 4 and PSA 4-20 sub-groups showed a superior Silhouette coefficients of 0.433 and 0.526 than that of the customized PHI cohort (0.432, 0.452). The PSA > 20 subgroup owned the highest Silhouette coefficient of 0.572. The validation cohort showed AUC values of 0.761, 0.823, 0.833 for these 3 sub-groups, with accuracy rates of 88.81%, 90.38%, and 82.05%.

Conclusion: In conclusion, our clustering model effectively categorizes patients into distinct risk groups with clear visualization and has demonstrated stability and reliability in the validation cohort, potentially aiding in early diagnosis of prostate cancer in clinical practice.

Background: Despite advancements in targeted therapy and immunotherapy, cutaneous melanoma continues to have a high mortality rate and poor prognosis, with therapies having limited efficacy in advanced melanoma. Therefore, it is crucial to develop novel therapeutics with proven clinical potential. In this study, we evaluated the efficacy of arcyriaflavin A (ArcA), a potent inhibitor of the cyclin D1/CDK4 complex, in suppressing aggressive phenotypes of metastatic melanoma.

Methods: The effects of ArcA on viability and cell cycle were evaluated across four melanoma cell lines: WM239A and its metastatic derivatives: 113-6/4L, 131/4-5B1, and 131/4-5B2. Additionally, we performed wound healing and transwell invasion assays, followed by western blot. We further established xenograft mouse models by subcutaneously injecting them with the four melanoma cell lines and measured tumor size and weight biweekly. Immunohistochemistry analysis was performed to compare protein expression.

Results: ArcA demonstrated dose-dependent cytotoxicity, selectively targeting melanoma cells without affecting normal cells, and induced G₁ cell cycle arrest. Moreover, ArcA significantly inhibited cell migration and invasion in metastatic melanoma cell lines, accompanied by reduced expression levels of p-GSK-3β (Ser9), MMP-9, and MMP-13, suggesting that its anti-metastatic effects may be partially mediated through GSK-3β, MMP-9, and MMP-13. These findings were further validated using mouse xenograft models; ArcA-treated mice exhibited significantly smaller tumor volumes and lighter tumor weights compared to vehicle-treated mice. Immunohistochemistry further confirmed decreased expression of p-GSK-3β, MMP-9, and MMP-13 in tumor tissues from ArcA-treated mice.

Conclusions: Collectively, our findings indicate that ArcA possesses substantial anti-tumor potential, including cytotoxic effects and inhibition of migration and invasion in metastatic melanoma. These results suggest that ArcA could enhance therapeutic efficacy in the treatment of metastatic melanoma.

Background: Breast cancer, a highly heterogeneous and complex disease, remains the leading cause of cancer-related death among women worldwide. Despite advances in treatment modalities, effective prognostic models and therapeutic strategies are still urgently needed.

Methods: We retrospectively analyzed 15 independent breast cancer cohorts to explore the role of RNA modifications in the prognosis of patients with breast cancer. By integrating nine types of RNA modifications, we developed a comprehensive machine learning-based RNA modification signature (CMRS). Furthermore, single-cell RNA sequencing data were analyzed to understand the biological mechanisms underlying CMRS. In addition, immune infiltration levels were evaluated via six different algorithms, and immune checkpoint inhibitor responsiveness was predicted. Moreover, the response of high-CMIS patients to chemotherapy was predicted via multiple datasets. Finally, immunohistochemistry was performed on tissue samples from breast cancer patients to validate protein expression levels.

Results: Our analysis revealed five key RNA modification-related genes (ENO1, ARAF, WT1, GADD45A, and BIRC3) associated with breast cancer prognosis. The CMRS model demonstrated high predictive accuracy across multiple cohorts and was significantly correlated with patient survival outcomes. Multiomics analysis revealed that high CMRS was associated with increased tumor mutational burden and distinct mutational signatures, particularly in pathways related to TP53, MYC, and cell proliferation. Single-cell analysis highlighted the involvement of epithelial cells and MYC signaling in high CMRS activity. Cell‒cell communication analysis revealed reduced interaction strength in hig CMRS patients, indicating poor prognosis. Furthermore, low CMRS patients presented increased immune cell infiltration and improved responsiveness to immune checkpoint inhibitors, whereas high CMRS patients were identified as potential candidates for treatment with panobinostat and vincristine.

Conclusion: Our study elucidates the significant role of RNA modifications in breast cancer prognosis and treatment. The CMRS model serves as a sensitive biomarker for predicting patient survival and treatment responsiveness, offering a new avenue for personalized therapy in patients with breast cancer.

Background: Breast cancer remains the most prevalent malignancy and the leading cause of cancer-related mortality among women worldwide. The primary factors contributing to the deterioration and death of patients with breast cancer are metastasis, recurrence, and drug resistance. These phenomena are closely related to the presence of breast cancer stem cells; however, the exact mechanisms regulating stemness remain to be elucidated. Rack1 (Receptor for Activated C Kinase 1), a well-known versatile scaffold protein, has been implicated in tumorigenesis and progression in numerous cancer types; however, its specific role in breast cancer stemness remains to be elucidated.

Methods: Using bioinformatic and immunohistochemical approaches, we validated that the expression level of Rack1 is associated with cancer stemness and affects the prognosis of patients. Through a series of experimental methods including mammosphere formation assay, flow cytometry, qPCR, Western blotting, and CHX assays, we validated at the molecular and cellular levels the mechanism by which Rack1 influences cancer stemness via the E2F1/SOX2 axis. Furthermore, by designing and utilizing lentiviral constructs to establish xenograft tumor models in mice, we further confirmed in vivo the impact of the Rack1/E2F1/SOX2 axis on the tumorigenic capacity of breast cancer cells.

Results: Our findings indicate that Rack1 plays a critical role in preserving the stemness characteristics of breast cancer cells. Mechanistically, the observed effects of Rack1 are achieved through the modulation of SOX2 expression, a master transcription factor that regulates cancer cell stemness and maintenance. We further demonstrate that Rack1 increases the stability of the E2F1 protein by inhibiting its ubiquitination and subsequent proteasome-mediated degradation, which in turn transcriptionally upregulates SOX2, thereby maintaining breast cancer cell stemness and tumorigenesis.

Conclusion: This study thus unveils a novel mechanism through which Rack1 executes its oncogenic function. This study also demonstrates that targeting the Rack1-E2F-SOX2 axis may be a potential strategy to inhibit breast cancer development and progression.

Background: Cancer cells undergo a metabolic shift termed the Warburg effect, transitioning from oxidative phosphorylation to aerobic glycolysis and promoting rapid tumor proliferation. Quinone oxidoreductase (NQO1), a cytosolic flavoprotein, is important for reprogramming cancer cell metabolism. Therefore, NQO1's function in aerobic glycolysis and impact on colorectal cancer (CRC) development and progression was investigated.

Methods: The clinical significance of NQO1 was evaluated by analyzing online databases and was substantiated in CRC specimens. NQO1's influence on proliferation, epithelial-mesenchymal transition (EMT), metastasis, apoptosis, and glycolytic pathways in CRC cells was evaluated using in vitro and in vivo experiments. The molecular interactions between NQO1 and microRNA-485-5p (miR-485-5p) were ascertained via quantitative reverse transcription PCR and dual luciferase reporter assays. The molecular mechanisms underlying the miR-485-5p/NQO1 axis and its effects on progression of malignancy and aerobic glycolysis in CRC cell lines were investigated.

Results: NQO1 promoted CRC cell proliferation and EMT, augmented their metastatic potential, and suppressed their apoptosis. The NQO1 overexpression-mediated enhancement of glycolytic activity is implicated in the increased proliferation, EMT, and metastatic abilities of, and reduced apoptosis in, CRC cells. Further, miR-485-5p may inhibit the proliferative and invasive traits of CRC cells by directly targeting the 3' untranslated region of NQO1 mRNA.

Conclusions: miR-485-5p/NQO1 signaling axis orchestrates aerobic glycolysis, thereby modulating CRC cell proliferation, metastasis, and apoptosis. Our study provides mechanistic perspectives regarding the role of NQO1 in CRC progression.