Journal of Cancer最新文献

Introduction: Despite rapidly improving therapeutics, challenges remain in the treatment of advanced breast cancer. Vinorelbine, a semisynthetic vinca alkaloid, is effective and well-tolerated in breast cancer treatment. The combination of vinorelbine and platinum-combination is a well-tolerated but underreported chemotherapy regimen. Bevacizumab, a VEGF-neutralizing antibody, has shown efficacy in HER2-negative metastatic breast cancer (mBC) when combined with chemotherapy. In this study we aimed to investigate the clinical and molecular effects of vinorelbine-platinum in heavily pretreated HER2-negative mBC, as well as the impact of adding bevacizumab. Material and methods: We conducted a retrospective study at Taipei Veterans General Hospital to evaluate the effectiveness of the vinorelbine-platinum regimen in heavily pretreated HER2-negative mBC patients from 2016 to 2020, with a portion of patients receiving additional bevacizumab. To model the molecular perturbations at a cellular level, transcriptional profiling of a triple negative breast cancer cell line treated with cisplatin-vinorelbine was done by RNA-sequencing. Results: The cohort included 54 patients. 50% of the patients received ≥ 5 lines of systemic treatment in the metastatic setting. All the patients had received anthracyclines and taxane. In patients treated with vinorelbine-platinum combination, the median progression-free survival (PFS) and overall survival (OS) were 2.3 and 7.3 months, respectively. With bevacizumab, median PFS improved to 4.1 months. Objective response rate (ORR) and disease control rate (DCR) without bevacizumab were 11.1% and 27.7%, respectively, improving to 25% and 83.3% with bevacizumab. Adverse events occurred in 37.0% of patients, with no grade IV events reported. Transcriptional profiling revealed significant downregulation of MAPK pathway, angiogenesis, and growth factor signaling related genes. Conclusion: The vinorelbine-platinum regimen, particularly with bevacizumab, shows potential efficacy even in heavily pretreated HER2-negative metastatic breast cancer patients. Molecular analyses of treated cells highlight potential targets and mechanisms of action, providing a basis for future therapeutic strategies.

Purpose: KLK7, also known as Kallikrein 7, is a secreted enzyme classified as a serine protease. Earlier studies have indicated that KLK7, KLK10, and KLK11 are linked to the survival rates and immune reactions of individuals with papillary thyroid cancer (PTC). This research examines KLK7, investigating its role and expression, and evaluates its viability as a treatment target for PTC. Methods: Initially, we examined the expression and possible functions of KLK7 in PTC using bioinformatics techniques. Researchers examined the impact of KLK7 on the cancer characteristics of PTC and explored if KLK7 influences the Epithelial-mesenchymal transition (EMT) process via the MAPK/ERK pathway in PTC using methods like immunohistochemistry and growth curve analysis. Ultimately, a model using a nude mouse was conducted to confirm the impact of KLK7 on PTC. Results: Our research demonstrated that KLK7 exhibited variations in THCA tissues, and KLK7-related genes had the role of participating in protein synthesis, genetic variation, mRNA degradation and immune microenvironment of PTC. KLK7 was upregulated in PTC tissues and positively associated with clinical stage and lymph node metastasis. Furthermore, the inhibition of KLK7 significantly diminished the proliferation, migration, and invasiveness of PTC cells. Notably, silencing KLK7 reduced phosphorylation of ERK1/2 and suppression of EMT. In vivo experiments further supported these findings. KLK7 might serve as an efficacious therapeutic target and predictive biomarker for PTC patients. Conclusion: KLK7 could be essential in the cancerous advancement of PTC by influencing the EMT via the MAPK/ERK signaling pathway, thereby impacting the growth, migration, and invasiveness of PTC cells. KLK7 appears to be a promising candidate for targeting in PTC therapy.

Acquired resistance to endocrine therapy is a major clinical challenge in the treatment of luminal A [estrogen receptor (ER)⁺ and/or progesterone receptor (PR)⁺, human epidermal growth factor receptor 2 (ERBB2/HER2)^-, and low Ki-67] breast cancer. Recently, molecular subtype conversion has been suggested as one of the possible causes of the development of drug-resistant breast cancer. However, the molecular mechanism underlying the molecular subtype conversion and the induction of endocrine therapy resistance in luminal A breast cancer is still incompletely understood. Here, we found that the ER⁺ MCF7-derived endocrine therapy-resistant MCF7-TamC3 breast cancer cells exhibit increased expression of an intrinsically disordered chromatin protein, NUPR1, compared to the parental luminal-A subtype like MCF7 breast cancer cells. Intriguingly, MCF7-TamC3 cells also exhibit characteristics that resemble the luminal B-ERBB2⁺ breast tumor subtype, like the increased expression of ERBB2 and the increased sensitivity to monoclonal ERBB2-targeting antibody Trastuzumab in vitro. Kaplan-Meier analysis of expression cohorts of breast tumors showed that high NUPR1 mRNA expression levels correlate with poor overall and relapse-free survival in both endocrine therapy-treated ER⁺ and ERBB2-enriched breast cancer patients. Results of the bioinformatics analysis showed that the NUPR1 mRNA expression level is also correlated with the clinical grading of the Tamoxifen-treated ER⁺ primary breast cancer. The qPCR and the western blot analysis results revealed that NUPR1 positively regulates the expression of the epigenetic regulator HDAC5, the anti-apoptotic molecule BIRC5, and the mitogenic receptor ERBB2 in MCF7-TamC3 and the ERBB2-enriched subtype like SK-BR-3 breast cancer cells. Downregulation of NUPR1 increased the sensitivity to estrogen deprivation in MCF7-TamC3 cells and decreased the viability of SK-BR-3 cells in vitro. These findings indicate that dysregulation of NUPR1 promotes the development of estrogen independence in ER⁺ breast cancer cells in part through expression regulation of HDAC5, ERBB2, and BIRC5. Targeting NUPR1 or its downstream regulating molecules may offer a potential strategy for overcoming resistance to endocrine therapy in patients with ER⁺ breast cancer.

A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) plays critical roles in various cancer-associated biological events, such as cell multiplication, migration, and metastasis. This study employs both the TCGA database and patient samples to demonstrate that ADAM10 is highly expressed in non-small cell lung cancer (NSCLC) compared with normal tissue at different stages. Increased ADAM10 expression is positively correlated with decreased overall and recurrence-free survival. On the functional front, overexpression of ADAM10 promotes lung cancer cell progression, migration, and invasion, whereas downregulation of ADAM10 inhibits these processes. Mechanically, ADAM10 modulates the expression of Notch1, MMP9 and EMT markers such as Vimentin, N-cadherin, and E-cadherin. Overall, our findings suggest that ADAM10 may be a promising therapeutic and prognostic marker for NSCLC, emphasizing the importance of regulating its expression.

Epigenetic, genetic predisposition and epidemiological risk factors were suggested to be involved in the carcinogenesis of oral cancer. In this study, we focused on the associations of MET single-nucleotide polymorphisms (SNPs) to oral cancer susceptibility and clinicopathological characteristics. The MET SNPs rs41736, rs41739, rs1621, and rs33917957 in 1198 controls and 1318 male patients with oral cancer were analyzed with real-time polymerase chain reaction. Our results revealed that the cigarette smokers among the oral cancer patients who carried the MET rs1621 polymorphic variant "G" were significantly associated with lower risk to develop oral cancer [OR (95% CI) = 0.463 (0.226-0.948)]. The male oral cancer patients who with the genotypic variant "G" of MET rs33917957 were associated with lower risk of cell differentiated grade (p = 0.041). In the TCGA database, the MET expressions were upregulated in oral cancer tissues compared to normal tissues, and were correlated with poor cell differentiated and poorer prognoses in smoker groups. In conclusion, these novel findings underscore the role of MET genetic variants in oral cancer susceptibility, particularly in smokers, and highlight the potential of these variants for prognosis and disease prediction.

Background: Ovarian cancer (OC) and cervical cancer (CC) are the leading causes of death among women. Therefore, identifying markers for early detection and treatment is critical. CDK1 governs the G2/M transition of the cell cycle and is a significant regulatory protein of the cycle. RO-3306 and UBE2C are related to CDK1 expression and might jointly facilitate the development of OC. CDK1 and CDK2 phosphorylate MLK3, which plays an important role in the invasion and proliferation of OC cells. Furthermore, miR-490-3P targets CDK1 and restrains the growth of ovarian tumors. CDK1 also plays a crucial part in the progression of CC. For instance, CDK1 overexpression can rescue the effect of RCC1 knockdown, which is involved in key processes, such as cytoplasmic transport, on G1 cell cycle progression. Using bioinformatics analysis, we evaluated the functional enrichment and role of the co-expressed gene CDK1 in these two cancers and its impact on their prognoses. Methods: First, we screened public datasets for OC- and CC-associated DEGs and identified intersecting genes. Enrichment analyses of these genes revealed key biological pathways and processes. We then generated protein-protein interaction networks to identify central genes and important gene modules. Results: Additional enrichment analyses revealed that cell cycle regulation and germ cell maturation were the primary processes regulated by these core genes. We also examined the function of CDK1 in OC and CC, demonstrating its overexpression and its association with particular immunological cell infiltration patterns. Furthermore, CDK1 mutational burden, copy number variation, and patient survival analyses indicated that CDK1 may be a useful prognostic marker. Finally, immunohistochemical examination confirmed the expression of some candidate genes in clinical samples. Conclusion: These findings shed light on the molecular causes of OC and CC and will aid the identification of novel targets for future research regarding these cancers, including their diagnosis and treatment.

Head and neck squamous cell carcinoma (HNSCC) is one of the most frequent cancers with a high mortality rate. Lactate accumulation, a hallmark of cancer, has received extensive attention, but its role in HNSCC remains underexplored. Therefore, we identified 33 prognostic genes related to lactate accumulation. By consensus clustering, we separated all HNSCC samples into cluster_A or cluster_B and explored the difference of clinicopathological characteristics and genomics landscape. Next, we performed LASSO analysis and RSF to calculate the lactate-related gene score (LRGS) and constructed a risk model with high accuracy for predicting survival, as estimated by ROC, nomogram, and calibration curve. Then, through OncoPredict algorithm and TCIA, we filter the suitable drugs, especially immunology with diverse LRGS. GSEA analysis showed that the DEGs of LRGS were enriched in activation of immune response and positive regulation of immune response. Moreover, we developed a tumor-infiltrating immune-related lncRNA signature (TILSig) through a combination of 115 immune cell lines from 16 GEO datasets and DealGPL570. Subsequently, we identified the 9 tumor-infiltrating immune-related lncRNAs and calculated the TIL_score. The correlations among these tumor-infiltrating immune-related lncRNAs, hub lactate-related genes and LRGS levels were visualized. According to validation using multiple datasets including TCGA, GSE65858, GSE41613, GSE27020, and the IMvigor 210 database, CARS2, NFU1, and SYNJ1 were identified as hub genes. In light of a comprehensive pan-cancer study, we analyzed these genes to detect the potential clinical value. In conclusion, the constructed LRGS provides important insights for subsequent mechanistic research and can guide clinicians in proposing therapeutic strategies for HNSCC patients.

Meningioma is the most common intracranial tumor. Sometimes, meningiomas can develop malignant transformation (MT). In this review, we review the incidence of MT of meningiomas. The incidence of MT of grade 2 meningiomas is likely to be higher than benign meningiomas. Approximately 1% to 4% of WHO Grade 1 meningiomas may undergo MT, while about 26% to 33% of Grade 2 meningiomas experience MT. Time to MT of grade 2 meningiomas seemed to be shorter than MT of grade 1 meningiomas. The time for Grade I meningiomas to undergo MT is approximately 5 years, while Grade II meningiomas typically experience MT in about 3 years. Several risk factors may be associated with MT, including non-skull base location, high mitotic Index, a larger primary tumor size, shorter recurrence time interval and male. Potential molecular mechanisms of MT include chromosomal abnormalities (Chromosome 22q deletion, NF2 gene mutation, loss of chromosome 1p), genomic alterations (FOXM1, CDKN2A/B and TERTp), and meningioma cancer stem cells. Secondary meningiomas may have poor tumor control rates and overall survival rates than primary meningiomas. Besides, the role of radiotherapy in MT of meningiomas is unclear. Major concerns are whether radiotherapy can induce MT of meningiomas, and whether radiotherapy can prolong time to MT through long term control of meningiomas. This review summarizes the MT of meningiomas, and may provide the direction for further study of meningiomas.

Background: Close clinical attention has been paid to triple-negative breast cancer (TNBC) due to its poor prognosis, high recurrence and mortality rates and rapid invasion and metastasis. The present study aimed to explore the potential mechanism of LINC00899 in the progression of TNBC and its effect on the proliferation and migration of TNBC cells via the microRNA (miR)-425/phosphatase and tensin homolog (PTEN) axis. Methods: For this purpose, plasma exosomes and related clinical data from 119 patients with breast cancer receiving neoadjuvant chemotherapy (59 patients with TNBC, 32 with HER2⁺ and with 28 luminal-type) and 20 healthy women were collected. Functional assays were then used to verify the role of the LINC00899/miR-425/PTEN axis in the proliferation and migration of TNBC cells. Results: The results showed that the expression of LINC00899 was reduced in plasma exosomes and breast cancer cell lines, which was associated with the Ki-67 index, tumor size and the presence or absence of lymph node metastasis but was not associated with patient age, androgen receptor expression or cholangiocarcinoma thrombus. The receiver operating characteristic curve results showed that LINC00899 had a high predictive value for the pathological outcome of patients with TNBC receiving neoadjuvant treatment. The results of the functional experiments also showed that LINC00899 targeted and regulated miR-425 in TNBC, and miR-425 negatively regulated the expression of PTEN. Conclusions: In conclusion, the results of the present indicated that LINC00899 may predict neoadjuvant chemotherapy efficacy in patients with TNBC and that LINC00899 inhibited the proliferation and migration of MDA-MB-231 cells via the miR-425/PTEN axis.

Background: Clear cell renal cell carcinoma (ccRCC) incidence and death have considerably changed in recent years. Our study aimed to investigate the incidence, survival, and tumor characteristics of ccRCC in the year of diagnosis. Methods: Our study participants were selected from the SEER database (2000-2017). Age-standardized incidence rates were calculated to compare incidence rates across time. In addition, we used Kaplan-Meier curves to calculate overall survival (OS) and Cox proportional hazards models to explore risk factors associated with mortality outcomes in patients with ccRCC. Results: In the SEER analysis from 2000 to 2017, the increasing trend in age-adjusted incidence of ccRCC has remained relatively stable over the years, increasing from 2.63 per 100,000 in 2000 to 8.79 per 100,000 in 2017. The increase in the incidence of patients at a localized stage plays a decisive role in the overall increase in the incidence of ccRCC. Conclusions: In the general population, patients diagnosed between 2009-2017 had a higher survival rate than those diagnosed between 2000-2008, which is consistent with all stages of the tumor. The incidence of ccRCC increases steadily with the year of diagnosis, while overall survival has significantly improved.