Cancer Biology & Therapy最新文献

Background: CASC21 was reported to be a hotspot gene in cervical cancer. The relationship between CASC21 genetic polymorphisms and cervical cancer has not been reported. Genetic factors influence the occurrence of cervical cancer. Thus, we explored the correlation between CASC21 polymorphisms and cervical cancer.

Methods: A total of 973 participants within 494 cervical cancer cases and 479 healthy controls were recruited. Five single nucleotide polymorphisms (SNPs) in the CASC21 gene were genotyped using the Agena MassARRAY platform. Chi-squared test, logistic regression analysis, odds ratio (OR), multifactor dimensionality reduction (MDR), and 95% confidence interval (95%CI) were used for data analysis.

Results: In the overall analysis, rs16902094 (p = .014, OR = 1.86, 95% CI = 1.12-3.08) and rs16902104 (p = .014, OR = 1.86, 95% CI = 1.12-3.09) had the risk-increasing correlation with the occurrence of cervical cancer. Stratification analysis showed that rs16902094 and rs16902104 were still associated with cervical cancer risk in the subgroups with age > 51, BMI < 24 kg/m², smokers, and patients with cervical squamous cell carcinoma. MDR analysis displayed that rs16902094 (.49%) and rs16902104 (.52%) were the main influential attribution factor for cervical cancer risk.

Conclusion: Our finding firstly determined that two CASC21 SNPs (rs16902094, rs16902104) were associated with an increased risk of cervical cancer, which adds to our knowledge regarding the effect of CASC21 on cervical carcinogenesis.

Triple-negative breast Cancer (TNBC) is an aggressive subtype lacking estrogen, progesterone, and HER2 receptors. Known for limited targeted therapies, it poses challenges and requires personalized treatment strategies. Differential analysis revealed a significant decrease in keratin 81 (KRT81) expression in non-TNBC samples and an increase in TNBC samples, lower KRT81 expression correlated with better TNBC patient outcomes. It emerged as an independent predictive factor for TNBC, with associations found between its expression and clinically relevant features. We further developed a nomogram for survival probability assessment based on Cox regression results, demonstrating its accuracy through calibration curves. Gene annotation analysis indicated that KRT81 is involved in immune-related pathways and tumor cell adhesion. KRT81 is associated with immune cell infiltration of Follicular helper T cells (Tfh) and CD8 + T cells, suggesting its potential impact on the immunological microenvironment. The study delved into KRT81's predictive value for immunotherapy responses, high expression of KRT81 was associated with greater potential for immune evasion. Single-cell RNA sequencing analysis pinpointed KRT81 expression within a specific malignant subtype which was a risk factor for TNBC. Furthermore, KRT81 promoted TNBC cell proliferation, migration, invasion, and adhesion was confirmed by gene knockout or overexpression assay. Co-culture experiments further indicated KRT81's potential role in inhibiting CD8 + T cells, and correlation analysis implied KRT81 was highly correlated with immune checkpoint CD276, providing insights into its involvement in the immune microenvironment via CD276. In conclusion, this comprehensive study positions KRT81 as a promising prognostic marker for predicting tumor progression and immunotherapy responses in TNBC.

Background: Chronic stress can induce stress-related hormones; norepinephrine (NE) is considered to have the highest potential in cancer. NE can stimulate the expression of hypoxia-inducible factor-1α (HIF-1α), which is associated with vascular endothelial growth factor (VEGF) secretion and tumor angiogenesis. However, the underlying mechanisms are poorly understood.

Methods: Tumor-bearing mice were subjected to chronic restraint stress and treated with normal saline, human monoclonal VEGF-A neutralizing antibody bevacizumab, or β-adrenergic receptor (β-AR) antagonist (propranolol). Tumor growth and vessel density were also evaluated. Human colorectal adenocarcinoma cells were treated with NE, propranolol, or the inhibitor of transforming growth factor-β (TGF-β) receptor Type I kinase (Ly2157299) in vitro. TGF-β1 in mouse serum and cell culture supernatants was quantified using ELISA. The expression of HIF-1α was measured using Real time-PCR and western blotting. Cell migration and invasion were tested.

Results: Chronic restraint stress attenuated the efficacy of bevacizumab and promoted tumor growth and angiogenesis in a colorectal tumor model. Propranolol blocked this effect and inhibited TGF-β1 elevation caused by chronic restraint stress or NE. NE upregulated HIF-1α expression, which was reversed by propranolol or Ly2157299. Propranolol and Ly2157199 blocked NE-stimulated cancer cell migration and invasion.

Conclusions: Our results demonstrate the effect of NE on tumor angiogenesis and the critical role of TGF-β1 signaling during this process. In addition, β-AR/TGF-β1 signaling/HIF-1α/VEGF is a potential signaling pathway. This study also indicates that psychosocial stress might be a risk factor which weakens the efficacy of anti-angiogenic therapy.

This study was designed to evaluate the diagnostic efficacy of relevant parameters of ¹⁸F-prostate-specific membrane antigen (PSMA)-1007 PET/CT in predicting the pathological grade of primary prostate cancer. Briefly, a prospective analysis was performed on 53 patients diagnosed with prostate cancer by systematic puncture biopsy, followed by ¹⁸F-PSMA-1007 PET/CT examination prior to treatment within 10 d. The patients were grouped in accordance with the Gleason grading system revised by the International Association of Urology Pathology (ISUP). They were divided into high-grade group (ISUP 4-5 group) and low-grade group (ISUP 1-3 group). The differences in maximum standardized uptake value (SUVmax), tumor-to-background ratio (TBR), intraprostatic PSMA-derived tumor volume (iPSMA-TV), and intraprostatic total lesion PSMA (iTL-PSMA) between the high- and low-grade group were statistically significant (p < .001). No significant difference was found for mean standardized uptake value (SUVmean) between the high- and low-grade groups (Z =  -1.131, p = .258). Besides, binary multivariate logistic regression analysis showed that only iPSMA-TV and iTL-PSMA were independent predictors of the pathological grading, for which the odds ratios were 18.821 [95% confidence interval (CI): 2.040-173.614, p = .010] and 0.758 (95% CI: 0.613-0.938, p = .011), respectively. The area under the ROC of this regression model was 0.983 (95% CI: 0.958-1.00, p < .001). Only iTL-PSMA was a significant parameter for distinguishing ISUP-4 and ISUP-5 groups (Z =  -2.043, p = .041). In a nutshell, ¹⁸F-PSMA-1007 PET/CT has good application value in predicting the histopathological grade of primary prostate cancer. Three-dimensional volume metabolism parameters iPSMA-TV and iTL-PSMA were found to be independent predictors for pathological grade.

Objective: Axitinib is an oral multi-target tyrosine kinase inhibitor used for the treatment of renal cell carcinoma (RCC). Because of the severe adverse events (AEs) associated with axitinib, patients often need dose reductions or discontinue its use, highlighting the need for effective biomarkers to assess efficacy and/or AEs. The aim of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) in genes involved in the pharmacodynamic action of axitinib and clinical prognosis and AEs in metastatic RCC (mRCC) patients.

Methods: This study included 80 mRCC patients treated with first-, second-, or third-line axitinib (5 mg orally twice daily). Clinical parameters and genetic polymorphisms were examined in 75 cases (53 males and 22 females). We assessed three SNPs in each of three candidate genes namely, angiotensin-converting enzyme (ACE), nitric oxide synthase 3 (NOS3), and angiotensin II receptor type 1 (AT1R), all of which are involved in axitinib effects on vascular endothelial function.

Results: Axitinib-treated patients carrying the ACE deletion allele suffered more frequently from hand-foot syndrome and a deterioration in kidney function (p  = .045 and p =  0.005, respectively) whereas those carrying the NOS3 G allele suffered more frequently from proteinuria and multiple AEs (p  = .025 and p =  0.036, respectively).

Conclusions: Our study found that the ACE deletion allele and the NOS3 G allele are associated with increased AEs.

While the emergence of immunotherapies has fundamentally altered the management of solid tumors, cancers exploit many complex biological mechanisms that result in resistance to these agents. These encompass a broad range of cellular activities - from modification of traditional paradigms of immunity via antigen presentation and immunoregulation to metabolic modifications and manipulation of the tumor microenvironment. Intervening on these intricate processes may provide clinical benefit in patients with solid tumors by overcoming resistance to immunotherapies, which is why it has become an area of tremendous research interest with practice-changing implications. This review details the major ways cancers avoid both natural immunity and immunotherapies through primary (innate) and secondary (acquired) mechanisms of resistance, and it considers available and emerging therapeutic approaches to overcoming immunotherapy resistance.

Substantial advancements have been made in recent years in comprehending immune memory, which enhances the secondary response through prior infections. The ability of vertebrate T and B lymphocytes to exhibit classic recall responses has long been regarded as a distinguishing characteristic. However, natural killer (NK) cells have been found to acquire immunological memory in a manner akin to T and B cells. The fundamental principles derived from the investigation of NK cell memory offer novel insights into innate immunity and have the potential to pave the way for innovative strategies to enhance therapeutic interventions against multiple diseases including cancer. Here, we reviewed the fundamental characteristics, memory development and regulatory mechanism of NK cell memory. Moreover, we will conduct a comprehensive evaluation of the accomplishments, obstacles, and future direction pertaining to the utilization of NK cell memory in the field of cancer immunotherapy.

Nephroblastoma, an overexpressed gene (NOV) protein, plays an important role in proliferation, differentiation, angiogenesis, adhesion, invasion and tumorigenesis, but the function of amino-truncated NOV is different. This study is to investigate the role of amino-truncated NOV in the progression of bladder cancer. Using immunohistochemistry and Western blot analysis, we detected the amino-truncated NOV in bladder cancer, and statistical analysis was performed to estimate the association between the expression of amino-truncated NOV and the patient's prognosis by SPSS 19.0. With transduction of amino-truncated NOV, we evaluated alteration for proliferation, migration, invasion and chemoresistance in bladder cancer cells, as well as some proteins related to Wnt/β-catenin pathway and epithelial-mesenchymal transition. The truncated variant of the NOV protein was located in a nucleus other than the cytoplasm and highly expressed in bladder cancer, which was also linked to higher pathological grade and positive lymph node metastasis as well as recurrence. The exact sequence of this truncated protein was confirmed, and it was a 26-kDa splicing. The truncated NOV protein found in bladder cancer was cut at the 187th amino acid of the full-length protein. It was also involved in bladder cancer progression and chemoresistance through a mechanism involving epithelial-mesenchymal transition (EMT) and the Wnt/β-catenin signaling pathway. Our findings provide experimental evidence that the nuclear NOV protein expression is a potential biomarker in the prognostic evaluation of bladder cancer and enhanced amino-truncated NOV expression is potentially important for bladder cancer cell invasion, metastasis and chemoresistance during progression.

Patients with advanced-stage cancers often suffer from severe pain caused by bone metastasis and destruction, for which effective treatment options are limited. Liu-Shen-Wan (LSW) is a widely recognized herbal formula utilized for pain relief. This study aims to elucidate the effects of LSW on bone cancer pain (BCP). In this study, the pharmacology of LSW on BCP was screened by network pharmacology. A BCP model was conducted using Walker 256 cells. Paw withdrawal threshold and paw withdrawal latency were employed as measures to assess the pain threshold in rats. The pathways and cell types of LSW against BCP were explored. Next, the impact of LSW on Walker 256 cells was evaluated, and UPLC-MS was utilized to identify the active ingredients of LSW. Furthermore, the effects of the key active ingredient, Bufalin, on the BCP rats were evaluated. There were 275 shared targets between LSW and BCP, which were enriched in neural tissue ligand-receptor interaction pathway. LSW increased pain threshold and decreased inflammatory cytokines levels in BCP rats by inhibiting PI3K/Akt and transient receptor potential vanilloid 1 (TRPV1) signaling through astrocytes and microglia. LY294002 further alleviated BCP in rats, while the effects were reversed after treatment with insulin-like growth factor 1 (IGF-1). Both LSW and its active ingredient Bufalin were shown to inhibit the viability and migration of Walker 256 cells and induce apoptosis. Bufalin appears to be the key active ingredient of LSW and exerts its pain-relieving effects by suppressing PI3K/Akt and TRPV1 signaling in BCP.

Thyroid cancer is one of the deadliest endocrine cancers, and its incidence has been increasing. While mutations in BRAF are common in thyroid cancer, advanced PTC patients currently lack therapeutic options targeting the MAPK pathway, and despite the approved combination of BRAF and MEK1/2 inhibition for BRAF-mutant ATC, resistance often occurs. Here, we assess growth and signaling responses to combined BRAF and MEK1/2 inhibition in a panel of BRAF-mutant thyroid cancer cell lines. We first showed that combined BRAF and MEK1/2 inhibition synergistically inhibits cell growth in four out of six of the -BRAF-mutant thyroid cancer cell lines tested. Western blotting showed that the MAPK pathway was robustly inhibited in all cell lines. Therefore, to identify potential mechanisms of resistance, we performed RNA-sequencing in cells sensitive or resistant to MEK1/2 inhibition. In response to MEK1/2 inhibition, we identified a downregulation of Aurora Kinase B (AURKB) in sensitive but not resistant cells. We further demonstrated that combined MEK1/2 and AURKB inhibition slowed cell growth, which was phenocopied by inhibiting AURKB and ERK1/2. Finally, we show that combined AURKB and ERK1/2 inhibition induces apoptosis in BRAF-mutant thyroid cancer cell lines, together suggesting a potential combination therapy for BRAF-mutant thyroid cancer patients.