Journal of Cancer最新文献

Background: Colorectal cancer (CRC) remains a leading cause of global cancer-related morbidity and mortality. Human Immunodeficiency Virus (HIV)-1 infection worsens colorectal cancer (CRC) outcomes. Methods: To investigate mechanisms, we conducted Tandem Mass Tag proteomics on tumor (C) and adjacent normal tissues (A) from five HIV-positive (HIV+) and four HIV-negative (HIV-) CRC patients. Four comparisons were analyzed: HIV+C vs HIV+A (differentially expressed proteins, (DEPs)-1), HIV-C vs HIV-A (DEPs-2), HIV+A vs HIV-A (DEPs-3), HIV+C vs HIV-C (DEPs-4) (|fold change| ≥ 2, p < 0.05). The DEPs specifically affected by HIV (DEPs-5) underwent KEGG pathway enrichment analysis. The relative abundance of pathway-associated DEPs was compared with the data from CPTAC database. Key DEPs were validated by western blot/immunohistochemistry. Results: We identified 749 (DEPs-1), 431 (DEPs-2), 4 (DEPs-3), and 21 (DEPs-4) DEPs. After excluding DEPs common to other comparisons, 592 HIV-specific DEPs (410 up-, 182 downregulated) were identified. KEGG enrichment revealed top altered pathways: upregulated ribosome (40 proteins) and downregulated complement and coagulation cascades (CCC pathway; 24 proteins). Comparison with the CPTAC database showed that HIV infection significantly increased the expression of upregulated DEPs but only slightly decreased the expression of downregulated ones. Downregulation of key CCC pathway proteins (C8B and SERPINA1) was confirmed by western blot and immunohistochemistry, respectively. Conclusion: HIV-associated CRC exhibits distinct proteomic alterations, particularly ribosome and CCC pathway dysregulation. C8B and SERPINA1 are potential biomarkers for HIV-CRC.

Serine/arginine-rich splicing factor 11 (SRSF11) is an RNA-binding regulator that modulates alternative splicing and RNA metabolism in a context-dependent manner across selected malignancies. Evidence from colorectal, hepatocellular, gastric, glioma, and a few other cancers indicates that SRSF11 participates in cell-cycle regulation, telomerase recruitment, and epithelial-mesenchymal transition (EMT) through specific signaling axes, including PAK5-SRSF11-HSPA12A in colorectal cancer, METTL3-SRSF11 in gastric and breast cancers, and SRSF11-CDK1/telomerase circuits in hepatocellular carcinoma. These mechanisms highlight SRSF11 as a candidate biomarker for diagnosis and prognosis rather than a universal oncogenic driver. We summarize the current mechanistic, post-translational, and non-coding RNA-mediated regulatory evidence, clarify the limitations of existing data, and propose future multi-omics and functional approaches to validate SRSF11-directed splicing therapy. This review integrates mechanistic insight with clinical evidence while emphasizing cancer-specific rather than generalized conclusions.

Prostate cancer (PCa) is a major health problem worldwide with variable incidence, progression and outcomes depending on genetic, environmental and socio-economic factors. This study compares gene expression profiles in PCa patients from South Africa (RSA) and the United States (USA) using RNA sequencing in whole blood and pathway analyses. Whole blood samples were collected in Wren RNA stabilization tubes from RSA-PCa (n = 6), RSA-controls (n = 6), USA-PCa (n = 7) and USA-Controls (n = 11). RNA sequencing revealed 1,627 differentially expressed genes (DEGs) in RSA-PCa vs. RSA-controls, and 2,193 DEGs in USA-PCa vs. USA-Controls. Pathway analyses identified geographical region-specific variations; RSA-PCa had upregulated myeloid suppressor cell pathways and immunosuppressive markers while USA-PCa samples exhibited upregulated cytokine signaling and inflammatory pathways. Comparative analysis of healthy controls revealed 2,280 DEGs, which indicated significant differences in molecular profile of the geographic locations. qRT-PCR undertaken on 27 biomarkers related to PCa in whole blood (PROSTest) identified that 26 (96%) of the marker genes were commonly expressed. RNAseq and normalized PCR gene expression of these markers were well-correlated (r = 0.44, p = 0.0012, n = 30 pairs). The results of this study indicate that there are geographic differences in blood-based gene expression in both controls and individuals with PCa. Genes associated with a clinically validated molecular assay (PROSTest) were identified in both populations, but significant differences in gene expression relevant to tumor pathobiology were identified. These immune-associated signaling pathways suggest differences between these two cohorts in blood-based molecular architecture related to PCa. They also suggest the need to consider population-specific biomarkers to better understand this disease. Ultimately, optimizing blood-based molecular diagnostic and therapeutic approaches will require population-level studies.

Objective: The association between long-term use of histamine-2 receptor antagonists and prostate cancer remains unclear. This study aimed to examine the age-specific risk of prostate cancer associated with long-term use of these medications. Methods: We conducted a nationwide case-control study using Taiwan's Health and Welfare Data Science Center database from 2003 to 2016. Men with newly diagnosed prostate cancer were matched to controls, and long-term use was defined as cumulative exposure of sixty days or more. Adjusted odds ratios were estimated using conditional logistic regression, controlling for comorbidities and medications. Results: Among 43,578 prostate cancer cases and 174,312 controls, long-term use of histamine-2 receptor antagonists was associated with a modest increase in prostate cancer risk, significant in men aged sixty-five and older (adjusted odds ratio = 1.087, 95% CI: 1.044-1.131) but not in younger groups. Cimetidine and ranitidine were each associated with increased risk in older men, while famotidine showed no significant association across age groups. Notably, cimetidine uses in men aged forty to sixty-four was associated with reduced prostate cancer risk (adjusted odds ratio = 0.865, 95% CI: 0.755-0.990), suggesting possible age-dependent effects. Conclusions: These findings suggest that long-term use of cimetidine and ranitidine may increase prostate cancer risk in older men, while famotidine was not associated with prostate cancer risk. Risk varies by age and drug type, highlighting the need for drug-specific evaluation in cancer pharmacoepidemiology.

Background: Tumor-infiltrating lymphocytes (TILs) are known to influence disease progression and treatment response in clear cell renal cell carcinoma. This study aimed at evaluating the prognostic and predictive relevance of T and B cell infiltration patterns in patients with metastatic clear cell renal cell carcinoma (mRCC-cc) treated sequentially with tyrosine kinase inhibitors (TKIs) and the immune checkpoint inhibitor nivolumab. Methods: In this retrospective cohort study, immune cell densities (CD3+, CD8+ T cells and CD20+ B cells) were analyzed by immunohistochemistry and quantified using digital image analysis software QuPath in distinct tumor regions of primary tumor: tumor center (TC), inner margin (IM), outer margin (OM), and peritumoral (PT) region. Samples were obtained from 36 patients with mRCC-cc treated with TKIs in the first line and sequentially with nivolumab in the second or third-line setting. Associations between immune cell densities, clinicopathological features, and survival outcomes were assessed using univariable and multivariable Cox regression models. Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were evaluated. Results: Densities of all immune cells were significantly higher in the OM and PT regions than in the TC and IM. Older age correlated with lower CD8+ T cell and CD20+ B cell densities, whereas higher tumor grade was associated with increased CD20+ B cell infiltration in IM. High CD20+ B cell density in IM and OM was significantly associated with shorter PFS during first-line TKI therapy (hazard ratio (HR) = 3.30, P = 0.015 and HR = 3.25, P = 0.016, respectively). In contrast, an intermediate CD8+ T cell density in the PT region was associated with longer PFS during sequential nivolumab treatment (HR = 0.26, P = 0.007). No significant associations between immune cell densities and ORR or OS were observed. Conclusions: Our findings suggest that spatial localization and density of tumor-infiltrating CD20+ B cells are potential predictors of poor PFS on TKIs, whereas higher CD8+ T cell infiltration in peritumoral areas may be a potential predictor of prolonged PFS on nivolumab. These immune-cell-based parameters may refine prognostic models and help guide treatment selection in mRCC-cc.

Prostate cancer (PCa) and breast cancer (BCa) are the leading causes of death in men and women in the US. Neurite outgrowth is a fundamental process in differentiating neurons and contributes to cancer progression. Snail transcription factor promotes cancer progression and regulates neurite outgrowth in PCa cells, but their molecular mechanisms are not fully understood. We hypothesize that Snail can stimulate neurite outgrowth through the secretion of extracellular vesicles. To test this hypothesis, we isolated exosomes from PCa (C4-2 non-silencing (NS) control and C4-2 Snail knockdown) and BCa (MCF7 Neo control and MCF7 Snail overexpressing) cells, which were confirmed by western blot analysis and Transmission Electron Microscopy. Proteomics of isolated exosomes from Snail-expressing C4-2 cancer cells shows predominantly Talin1 proteolyzed C-terminal rod domain and N-terminal head domain within exosomes, while full-length Talin1 is found in whole cell lysates. A significantly higher percentage of NPC (Neural Progenitor Cells) with neurite outgrowth is observed when cultured with conditioned medium or exosomes collected from C4-2 NS PCa or MCF7 Snail BCa cells expressing high levels of Snail compared to C4-2 Snail knockdown or MCF7 Neo, respectively. A similar trend is observed for increased average neurite length due to Snail expression. Furthermore, we find that mH₄, a specific inhibitor of proteolyzed Talin1, reduces Snail-induced neurite outgrowth and AKT activation within neurons. Overall, Snail may promote cancer-nerve interactions via Talin1, indicating that Talin1 inhibitors can be a potent targeted therapy in malignant tumors with neurite outgrowth.

Objective: Immunotherapy can be accompanied by cutaneous adverse events that negatively impact the patient's quality of life (QoL). This trial aimed to evaluate the efficacy of two novel skin care products in preventing and managing cutaneous adverse events associated with immunotherapy. Methods: An interventional, open-label, single-group, pretest-posttest study was conducted at the Jessa Hospital (Belgium) involving cancer patients receiving immunotherapy (n=75). Patients applied the skin care products daily for three weeks. A researcher evaluated skin toxicity using the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0. Questionnaires assessed the frequency and severity of their symptoms (Numeric Rating Scale, NRS), the patient's QoL (Dermatology Life Quality Index, DLQI, and Skindex-29), the Patient Benefit Index, and patient satisfaction (NRS). Results: The CTCAE and NRS showed that pruritus and xerosis were the most frequently observed skin toxicities. According to the NCI-CTCAE, an improvement was detected in the grade of pruritus and xerosis after applying the novel emollients (P<0.001). All patient-reported symptoms decreased significantly in frequency. Both the Skindex-29 total score (P<0.001) and DLQI (P=0.038) improved over time. Moreover, 42.7% of the patients experienced at least one patient-relevant benefit of the treatment. Lastly, 70.7% of the patients were satisfied with the products, and 74.6% would recommend them to other patients. Conclusion: This trial demonstrates that the two novel emollients effectively alleviate immunotherapy-related dermatological toxicities. As a result, an improvement in the patient's QoL was observed, accompanied by high satisfaction and a strong likelihood of recommendation. Future research with a control group is necessary to draw firm conclusions.

Cisplatin remains a standard first-line therapy for epithelial ovarian cancer; however, chemoresistance leads to poor prognosis and high recurrence. Analysis of The Cancer Genome Atlas confirmed improved overall survival in cisplatin-sensitive tumors, underscoring the need for strategies to overcome resistance in clinical settings. Integrative bioinformatics of cisplatin-treated ovarian cancer datasets from the Gene Expression Omnibus (n=255) identified six molecular drivers of resistance: Kaiso (ZBTB33), pregnane X receptor (PXR), NF-κB, HER2 (ERBB2), P-glycoprotein (P-gp/ABCB1), and HIF1A. These targets were validated in ovarian tumor specimens via immunohistochemistry, confirming elevated expression in chemo-resistant disease. Additionally, the quantitative real-time PCR analysis confirms the transcriptional upregulation of the six resistance-associated genes in cisplatin-resistant SKOV3 and OVCAR-5 ovarian cancer cells, consistent with the immunohistochemistry findings. The average fold change in mRNA transcripts ranged from 2.4 for P-glycoprotein to 5 for both NF-kB and Kaiso. Although less well studied in ovarian cancer, Kaiso is known to regulate EMT and tumor invasion in other solid tumors. Functional studies using SKOV3 and OVCAR-5 cell lines demonstrated that knockdown of Kaiso via RNA interference significantly increased cisplatin-induced cell death, indicating a direct role in therapeutic resistance. Furthermore, we investigated the synergistic effects of combining stearidonic acid (SDA), a plant-based omega-3 fatty acid known to inhibit NF-κB, with cisplatin on cell death in SKOV3 and OVCAR-5 cell lines, and compared the results with those of each compound used individually. Interestingly, co-treatment with stearidonic acid (SDA) synergistically enhanced the cytotoxicity of cisplatin at a lower dose in both cell models. These findings reveal a clinically relevant resistance signature and highlight the therapeutic potential of combinatorial strategies that target both transcriptional regulators (e.g., Kaiso) and inflammatory signaling (e.g., NF-κB). Dual targeting of these pathways may resensitize tumors to cisplatin and improve outcomes for patients with advanced ovarian cancer.

Glioblastomas represent the most prevalent primary brain tumors in adults. Due to their highly malignant biological behavior, they are classified as grade 4 according to the World Health Organization (WHO) classification of brain tumors. Despite the progress in understanding the molecular pathogenesis of these tumors, no curative therapy has been developed for patients with glioblastoma. In this study, an integrated comparative analysis of cyclin-dependent kinase inhibitor (CDKN) 2A/B chromosomal deletion was performed on 45 glioblastomas, representing the most frequent molecular subtypes of glioblastomas, receptor tyrosine kinase (RTK) I (n=13), RTK II (n=15), and the mesenchymal subtype (MES) (n=17). The analysis of copy number variation (CNV) profiles was conducted on CDKN2A/B losses. Subsequent statistical analysis was then applied to correlate the collected data with molecular glioblastoma epigenotypes. Loss of CDKN2A/B was found 44% (20/45) of all glioblastomas, thereby, in 46% (6/13) of RTK I, 67% (10/15) RTK II, and 24% (4/17) of MES. Statistical analysis showed that loss of CDKN2A/B is significant (p < 0.01) in RTK II compared with MES. Even though CDKN2A/B does not per se function as a molecular target, there is great potential for enhancing treatment outcomes through the restoration of the tumor-suppressing capabilities of CDKN2A/B. This strategy can be employed in therapeutic interventions and is a promising avenue for research. This efficacy of this approach demonstrates high potential, as evidenced by its efficacy in other tumors, including melanoma.

Cancer stem cells (CSCs) play pivotal roles in tumor relapse, metastasis, and therapy resistance. Interleukin 17 receptor A (IL-17RA) is a key mediator in colorectal cancer (CRC) pathogenesis and progression. Our recent study demonstrated that reduced IL-17RA expression correlates with favorable prognosis in CRC patients and suppresses tumor growth in murine models. This study aimed to investigate the role of IL-17RA in promoting cancer stem-like properties and its impact on colorectal cancer prognosis and chemoresistance. Expression levels of IL-17RA and CSC markers in CRC cells were evaluated using quantitative real-time polymerase chain reaction and Western blotting. Kaplan-Meier analysis of 68 CRC patients revealed that high IL-17RA expression is associated with poor clinical outcomes. To investigate IL-17RA's functional role, CRC cells with stable IL-17RA overexpression were analyzed for changes in CSC marker expression, sphere formation, and 5-fluorouracil (5-FU) resistance. IL-17RA overexpression significantly increased CSC marker expression, including cluster of differentiation 133 (CD133), leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), sex determining region Y-box 2 (SOX2), and enhanced tumor sphere formation and 5-FU resistance in SW620 cells. Specific inhibitors of IL-17RA signaling, such as the STAT3 inhibitor Stattic, reduced the expression of CD133, LGR5, ALDHA1, SOX2 and c-MYC, as well as tumor sphere formation in SW620 cells. These findings elucidate a novel IL-17RA-STAT3 axis that regulates CSC properties in CRC and highlight IL-17RA as a promising prognostic biomarker and therapeutic target for CRC treatment.