BACKGROUND/AIM:Notch signaling exerts context-dependent effects in cancer; however, the prognostic relevance of inherited variation in Notch-related genes in prostate cancer remains unclear. We investigated whether germline single-nucleotide polymorphisms (SNPs) in Notch pathway genes are associated with clinical outcomes in men receiving androgen deprivation therapy (ADT). PATIENTS AND METHODS:We genotyped 222 SNPs across 24 Notch pathway-related genes in 630 patients with advanced prostate cancer. Associations with cancer-specific survival (CSS) and overall survival (OS) were assessed using Cox proportional hazards models. Integrative bioinformatics analyses, including pooled transcriptomic dataset analysis, expression quantitative trait locus analysis, and pathway enrichment, were performed to assess functional relevance. RESULTS:Multiple SNPs were significantly associated with CSS and OS, with Yes1-associated transcriptional regulator (YAP1) rs1894116 showing the strongest prognostic signal. The minor G allele was associated with a 26% reduction in prostate cancer-specific mortality and a 22% reduction in all-cause mortality, independent of established clinical predictors. Functional annotation suggested that rs1894116 may be linked to increased YAP1 expression. Pooled transcriptomic analyses showed lower YAP1 expression in tumors than in normal tissue, while higher YAP1 expression correlated with more favorable outcomes. YAP1-correlated genes were enriched in the focal adhesion pathway, suggesting a tumor-suppressive YAP1-focal adhesion axis, particularly involving vinculin. CONCLUSION:Germline variation in the Notch-YAP axis, notably YAP1 rs1894116, predicts survival in patients with prostate cancer treated with ADT. Elevated YAP1 expression and coordinated activation of focal adhesion components may be associated with less aggressive disease. These findings provide mechanistic insight into Notch signaling in prostate cancer and highlight YAP1 and its variants as potential biomarkers for risk stratification and personalized therapy.

Diisononyl cyclohexane-1,2-dicarboxylate (DINCH), a non-phthalate plasticizer adopted as a safer alternative for food-contact and medical-grade materials, is ubiquitously detected in human biomonitoring studies. Despite widespread exposure, its transcriptional effects in prostate cells and the potential prostate cancer relevance of DINCH-responsive genes remain unclear. We integrated transcriptomic profiling of DINCH-exposed human prostate epithelial cells with exploratory genetic association analyses in 630 patients with prostate cancer receiving androgen deprivation therapy (ADT). Haplotype-tagged single-nucleotide polymorphisms (SNPs) in candidate DINCH-responsive genes were evaluated for their association with overall survival (OS) and cancer-specific survival (CSS). The prostate cancer relevance of the prioritized genes was further validated using pooled multi-cohort bioinformatic analyses. DINCH exposure produced an exploratory molecular signature comprising 83 genes across all tested doses, broadly suppressing cell–matrix adhesion pathways and activating chromatin remodeling. Exploratory genetic screening identified nominal associations of LPP rs1040033 with OS (p = 0.0002, q = 0.131) and FAM111B rs7110278 with CSS (p = 0.0010, q = 0.575); neither association remained significant after multiple-testing correction. DINCH exposure significantly downregulated LPP and upregulated FAM111B expression in prostate epithelial cells. Independently, pooled analyses demonstrated reduced LPP and elevated FAM111B expression in prostate cancer tissues compared with normal prostate tissues. Higher LPP expression predicted a favorable prognosis, whereas elevated FAM111B predicted worse survival. Pathway analyses linked low LPP expression to impaired adhesion signaling and metabolic reprogramming, whereas high FAM111B expression was associated with mitotic and cell-cycle activation. DINCH exposure induced exploratory transcriptional alterations involving LPP-related adhesion pathways and FAM111B-related proliferative signaling. The genetic findings are exploratory and require independent validation. Although public datasets support the prognostic relevance of LPP and FAM111B in prostate cancer, they do not link these genes to DINCH exposure.

Deltamethrin (DLT), a type-II pyrethroid insecticide, can interfere with voltage-gated Na+ currents (INa) in excitable cells; however, its effects on INa gating and neuronal discharge remain unclear. Using Neuro-2a motor neuron-like cells and whole-cell patch-clamp recordings, we found that DLT (10 μM) mildly increased transient INa (INa(T)) but markedly enhanced late INa (INa(L)) and tail INa (INa(Tail)). In the continued presence of DLT, dapagliflozin (Dapa) counteracted the DLT-induced increases in INa(L) and INa(Tail). We further incorporated modified INa(T), INa(L), and INa(Tail) kinetics mimicking DLT effects into a computational model of respiratory neurons. The simulations generated two distinct action potential (AP) bursting patterns characterized by either slow or fast intraburst firing. Both patterns exhibited progressively shortened AP intervals within bursts, indicating reverse spike-frequency adaptation. Molecular docking further predicted hydrophobic interactions between DLT and the NaV1.8 channel. Collectively, these findings demonstrate that DLT preferentially enhances INa(L) and INa(Tail), which may substantially alter bursting behavior in modeled respiratory neurons.

Background/Objective: Di-2-ethylhexyl phthalate and its bioactive metabolite mono-2-ethylhexyl phthalate (MEHP) are ubiquitous endocrine-disrupting chemicals implicated in carcinogenesis. However, the molecular mechanisms linking MEHP exposure, host genetic susceptibility, and prostate cancer progression remain incompletely defined. Methods: We integrated transcriptomic profiling of MEHP-exposed human prostate epithelial cells with a genetic association study of 630 patients with prostate cancer receiving androgen deprivation therapy. MEHP-responsive genes were identified from public microarray datasets and subjected to pathway enrichment analyses. Germline single-nucleotide polymorphisms (SNPs) in MEHP-regulated genes were evaluated for their association with progression-free survival, overall survival, and cancer-specific survival. The clinical and functional relevance of the key genes was further assessed using large-scale public prostate cancer expression datasets. Results: MEHP exposure induced widespread transcriptional reprogramming, prominently suppressing focal adhesion and cell-matrix interaction pathways. Genetic analyses identified multiple prognostically relevant SNPs within MEHP-responsive genes, with anoctamin 4 (ANO4) variants showing consistent associations across all clinical endpoints. The minor allele of rs17485225 in ANO4 was significantly associated with reduced all-cause and prostate cancer-specific mortality. Pooled analyses revealed reduced ANO4 expression levels in prostate cancer tissues and improved survival in patients with high ANO4 expression levels. Pathway analyses linked low ANO4 expression levels with enhanced cell cycle activity and compromised cell adhesion. Conclusions: Our findings suggest that ANO4 may act as a mediator of MEHP-associated prostate cancer progression and support a gene-environment interaction model in which environmental toxicant exposure and germline variation converge on focal adhesion dysregulation to potentially contribute to aggressive disease.

The ZZ-type zinc-finger family has emerged as an important regulator of tumorigenesis; however, its roles in renal cell carcinoma (RCC) susceptibility and prognosis are largely unexplored. This study aimed to systematically evaluate the genetic variants within this gene family to identify novel risk drivers and elucidate their downstream pathogenic networks. A total of 148 single-nucleotide polymorphisms (SNPs) were genotyped across 17 ZZ-type zinc finger genes in a cohort of 630 Taiwanese participants (312 patients with RCC and 318 healthy controls). The results were validated using pooled transcriptomic analysis of 18 independent datasets. Weighted gene co-expression network analysis (WGCNA) was used to construct tumor-specific networks and identify key driver genes. The Asian-specific variant of KCMF1 rs146409312 emerged as a significant susceptibility locus. The minor A allele conferred a 3.38-fold increased risk of RCC (adjusted odds ratio = 3.22, 95% confidence interval = 1.57-6.58, p = 0.001). KCMF1 was consistently upregulated in tumor tissues and was associated with poor patient survival. WGCNA identified a clinically relevant KCMF1-associated gene module enriched in ribosomal biogenesis and MYC target signaling. Within this network, SNRPD2 was identified as a critical hub gene, and its overexpression was strongly correlated with advanced tumor grade, stage, and reduced overall survival (p < 0.001). In conclusion, KCMF1 rs146409312 was identified as a potent, population-specific risk factor for RCC. A pathogenic KCMF1-driven network converging on SNRPD2 was delineated, offering novel insights into RCC etiology and highlighting potential biomarkers for prognostic stratification.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, highlighting the urgent need for novel therapeutic strategies. In this study, we investigated the anticancer activity and molecular mechanism of ent-9α,11α-dihydroxy-15-oxo-kaur-16-en-19-oic acid (9α,11α-dihydroxy-kaurenoic Acid; 9α,11αOH-KA, also known as adenostemmoic acid B), a natural kaurane-type diterpenoid isolated from Adenostemma lavenia, against NSCLC. 9α,11αOH-KA exhibited potent and preferential cytotoxicity toward NSCLC cells compared with non-tumorigenic fibroblasts, accompanied by inhibition of cell migration and induction of apoptosis. Moreover, 9α,11αOH-KA significantly suppressed tumorsphere formation and reduced the expression of cancer stem cells (CSCs)-associated markers, including CD44, CD133, and Notch-1, indicating impairment of stemness-associated properties. Mechanistically, 9α,11αOH-KA induced mitochondrial dysfunction associated with impaired oxidative phosphorylation (OXPHOS), as evidenced by reduced basal and maximal oxygen consumption rate (OCR), depletion of intracellular ATP, and dissipation of mitochondrial membrane potential. These mitochondrial alterations were accompanied by pronounced reactive oxygen species (ROS) accumulation, which contributed to apoptotic cell death, as antioxidant pretreatment attenuated both ROS generation and apoptosis. Importantly, oral administration of 9α,11αOH-KA significantly suppressed A549 xenograft tumor growth without observable systemic toxicity. Collectively, 9α,11αOH-KA exhibits strong anti-NSCLC activity through dual suppression of mitochondrial bioenergetics and CSCs-associated properties. These findings highlight 9α,11αOH-KA as a promising phytochemical candidate for the development of mitochondria-targeting therapeutics for NSCLC.

Background/Objectives: Prostate cancer is one of the most common malignancies among men worldwide, and clinical outcomes following androgen deprivation therapy (ADT) vary considerably. Given that endoplasmic reticulum (ER) stress and the unfolded protein response mediate processes such as apoptosis, tumor adaptation, and disease progression, we aimed to investigate whether genetic variants in ER stress-related genes are associated with survival outcomes in patients with prostate cancer receiving ADT. Methods: This study enrolled 630 patients with prostate cancer who underwent ADT across three medical centers in Taiwan. A genetic association analysis of 89 haplotype-tagged single-nucleotide polymorphisms (SNPs) across 12 ER stress-related genes was performed. The primary clinical endpoint was overall survival (OS). Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate prognostic associations. Furthermore, publicly available databases were integrated to analyze gene expression, clinical relevance, gene set enrichment, and tumor immune infiltration to elucidate the underlying biological mechanisms. Results: Among the analyzed SNPs, BAX rs182509214 showed the strongest association with OS. The minor G allele of BAX rs182509214 was significantly associated with poorer OS. Prostate tumor tissues exhibited markedly elevated BAX expression compared with normal prostate tissues, and this elevated expression was associated with worse survival outcomes. Multiple public gene expression datasets confirmed the overexpression of BAX in prostate cancer. Functional analyses revealed that genes associated with BAX expression were predominantly enriched in ribosomal, oxidative phosphorylation, and proteasomal pathways. Furthermore, the BAX copy number variation was significantly associated with the infiltration levels of multiple immune cell types, and BAX expression was negatively correlated with CD8+ T-cell infiltration, implying a potential marker role for the tumor immune microenvironment. Conclusions: The ER stress-related genetic variant, BAX rs182509214, may influence survival outcomes in patients with prostate cancer receiving ADT. BAX alterations are associated with disease progression and linked to mitochondria-related metabolic pathways and the tumor immune microenvironment. These results highlight BAX as a potential prognostic biomarker for prostate cancer treated with ADT; however, further validation in larger cohorts and functional studies is warranted.

YAP is a transcription cofactor in the Hippo pathway that interacts with the TEAD family of transcription factors in the nucleus to promote CTGF expression and stimulate cell growth. YAP hyperactivation is frequently observed in fibrotic diseases. The main kinases in the Hippo pathway, MST1/2, a member of the STE20 family, promote Lats phosphorylation, leading to YAP phosphorylation, which prevents its nuclear entry and thus inhibits cell growth. High cell density induces Lats phosphorylation, causing YAP phosphorylation and its exclusion from the nucleus. Additionally, energy stress, such as glucose deprivation, induces AMPK phosphorylation, which also prevents YAP from entering the nucleus. MST3, another member of the STE20 family, has been shown to regulate cell apoptosis, migration, polarization, and ion homeostasis in previous studies. We hypothesized that MST3 is involved in Hippo pathway-mediated fibrosis. To test this, we overexpressed HA-tagged MST3 (HA-MST3) and a kinase-dead mutant (HA-MST3-KD) in MDCK cells. When cells reached a high density, HA-MST3 was activated to phosphorylate YAP, promoting its nuclear exit and inhibiting cell growth. In contrast, HA-MST3-KD cells showed reduced phosphorylated YAP, resulting in YAP retention in the nucleus, continuous cell growth, and NIH/3T3 cell fibrosis. Interestingly, YAP did not exit the nucleus in HA-MST3-KD cells treated with the YAP inhibitor verteporfin, but it did exit under metformin treatment due to energy stress, accompanied by increased AMPK and YAP phosphorylation, which inhibited MST3-KD-mediated fibrosis. These findings suggest that metformin-induced AMPK activation could provide a therapeutic approach for MST3-KD-mediated fibrosis.

Biochemical recurrence (BCR) is a critical concern in prostate cancer management; however, its underlying genetic determinants remain poorly understood. The aldehyde dehydrogenase 1 (ALDH1) gene family is involved in cellular detoxification and biosynthetic processes and has been implicated in various cancers. This study investigated the association between the ALDH1 family members and prostate cancer recurrence. We conducted a two-stage genetic association study involving 134 single-nucleotide polymorphisms within the ALDH1 family to assess their association with BCR-free survival in prostate cancer. Gene set and pathway enrichment analyses were performed to explore the biological relevance of significant genes across multiple datasets. ALDH1A2 rs16939929 showed a robust association with BCR-free survival in both discovery and replication cohorts. Functional analyses indicated that rs16939929 affected ALDH1A2 expression in various tissues. Pooled analysis of 42 prostate cancer gene expression datasets revealed that ALDH1A2 expression was significantly lower in prostate cancer tissues and higher expression was associated with better patient prognosis. Enrichment analyses revealed that ALDH1A2 was co-expressed with genes primarily involved in cell adhesion pathways. Further analysis confirmed that several of these co-expressed cell adhesion molecules were associated with improved patient survival. In addition, ALDH1A2 expression was associated with increased immune cell infiltration into the prostate cancer microenvironment. In conclusion, ALDH1A2 rs16939929 is a significant predictor of BCR-free survival in prostate cancer, potentially through its effects on the gene expressions of ALDH1A2 and cell adhesion molecules. These findings suggest that ALDH1A2 plays a tumor-suppressive role in prostate cancer progression.

The core subunits of the KV7.2, KV7.3, and KV7.5 channels, encoded by the KCNQ2, KCNQ3, and KCNQ5 genes, are expressed across various cell types and play a key role in generating the M-type K+ current (IK(M)). This current is characterized by an activation threshold at low voltages and displays slow activation and deactivation kinetics. Variations in the amplitude and gating kinetics of IK(M) can significantly influence membrane excitability. Notably, IK(M) demonstrates distinct voltage-dependent hysteresis when subjected to prolonged isosceles-triangular ramp pulses. In this review, we explore various small-molecule modulators that can either inhibit or enhance the amplitude of IK(M), along with their perturbations on its gating kinetics and voltage-dependent hysteresis. The inhibitors of IK(M) highlighted here include bisoprolol, brivaracetam, cannabidiol, nalbuphine, phenobarbital, and remdesivir. Conversely, compounds such as flupirtine, kynurenic acid, naringenin, QO-58, and solifenacin have been shown to enhance IK(M). These modulators show potential as pharmacological or therapeutic strategies for treating certain disorders linked to gain-of-function or loss-of-function mutations in M-type K+ (KV7x or KCNQx) channels.

Background: Prostate cancer is a major global health burden, with biochemical recurrence (BCR) following radical prostatectomy affecting 20-40% of patients and posing significant challenges to prognosis and treatment. Emerging evidence suggests a critical role for differentially expressed in normal and neoplastic cell (DENN) domain-containing genes in oncogenesis; however, their implications in prostate cancer and BCR risk remain underexplored. Methods: This study systematically evaluated 151 single-nucleotide polymorphisms in DENN domain-containing genes in 458 patients with prostate cancer and BCR, followed by validation in an independent cohort of 185 patients. Results: Multivariate Cox regression analyses identified DENND2D rs610261 G>A as significantly associated with improved BCR-free survival in both cohorts (adjusted hazard ratio = 0.39, 95% confidence interval = 0.23-0.66, p = 0.001). Functional analysis revealed rs610261's regulatory potential, with the protective A allele correlating with increased DENND2D expression in various human tissues. Compared to normal prostate tissues, DENND2D expression was reduced in prostate cancer, with higher expression being linked to favorable patient prognosis (p = 0.03). Gene set enrichment analysis revealed an association between DENND2D expression and the negative regulation of MYC target genes, including MAD2L1, ERH, and CLNS1A, which are overexpressed in prostate cancer and associated with poor survival. Furthermore, the elevated DENND2D expression promotes immune infiltration in prostate cancer, supporting its role in immune modulation. Conclusions: DENND2D is a prognostic biomarker for BCR in prostate cancer and offers new avenues for personalized treatment strategies.

Background/Objective: Biochemical recurrence (BCR) after radical prostatectomy (RP) for prostate cancer indicates disease progression. Although type 2 diabetes mellitus (T2D) shows a paradoxical association with prostate cancer risk, the prognostic role of T2D-related genetic variants remains unclear. Methods: We analyzed 113 common T2D susceptibility-related single-nucleotide polymorphisms (SNPs) in 644 Taiwanese men with localized prostate cancer (D’Amico risk classification: 12% low, 34% intermediate, and 54% high) treated with RP. Associations between SNPs and BCR were assessed using Cox regression, adjusting for key clinicopathological factors. Functional annotation was performed using HaploReg and FIVEx, while The Cancer Genome Atlas transcriptomic data were analyzed for C2 calcium-dependent domain-containing 4A (C2CD4A) expression. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were applied to explore related biological pathways. Results: C2CD4A SNP rs4502156 was independently associated with a reduced risk of BCR (hazard ratio = 0.80, p = 0.035). The protective C allele correlated with higher C2CD4A expression. Low C2CD4A expression is associated with advanced pathological stages, higher Gleason scores, and disease progression. GSEA revealed negative enrichment of mitotic and chromatid segregation pathways in high-C2CD4A-expressing tumors, with E2F targets being the most suppressed. GSVA confirmed an inverse correlation between C2CD4A expression and E2F pathway activity, with CDKN2C as a co-expressed functional gene. Conclusions: The T2D-related variant rs4502156 in C2CD4A independently predicts a lower risk of BCR, potentially via suppression of the E2F pathway, and may serve as a germline biomarker for postoperative risk stratification.

BACKGROUND/AIM:Prostate cancer remains a major global health burden, with treatment resistance posing a significant challenge. Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), a histone methyltransferase, is frequently overexpressed in prostate cancer, contributing to tumor progression and castration resistance. Clinical trials of EZH2 inhibitors may have therapeutic benefits. This study aimed to evaluate the impact of genetic variants in EZH2-related genes on survival outcomes in prostate cancer. PATIENTS AND METHODS:We conducted a genetic association study evaluating 76 single nucleotide polymorphisms (SNPs) across 10 EZH2-related genes in 630 patients with prostate cancer undergoing androgen deprivation therapy (ADT). Functional analyses, including gene ontology and pathway enrichment assessments, were performed to elucidate the biological significance of key genes across multiple datasets. RESULTS:DNMT3A rs77993651 was significantly associated with both cancer-specific survival [hazard ratio (HR)=0.82, p=0.042] and overall survival (HR=0.80, p=0.011). Functional annotation indicated that rs77993651 resides within enhancer histone marks, potentially regulating DNMT3A expression. Elevated DNMT3A expression was observed in prostate tumor tissues and correlated with more aggressive features and shorter progression-free survival. Gene set enrichment analysis revealed that DNMT3A expression was strongly associated with cell cycle G2/M checkpoint regulation, implicating a role in prostate cancer progression. CONCLUSION:The prognostic significance of DNMT3A and its genetic variant rs77993651 in prostate cancer is herein highlighted. Targeting DNMT3A-mediated pathways may offer novel therapeutic strategies for prostate cancer management.

BACKGROUND/AIM:Prostate cancer, a leading global malignancy, exhibits variable progression influenced by angiogenesis, the formation of new blood vessels critical for tumor growth and metastasis. We investigated the impact of genetic variants of angiogenesis-related genes on the survival outcomes of patients with prostate cancer receiving androgen deprivation therapy (ADT). MATERIALS AND METHODS:We conducted a genetic association study of 87 single-nucleotide polymorphisms across seven angiogenic genes in 630 patients with prostate cancer undergoing ADT. Survival analysis was used to assess progression-free survival (PFS) and overall survival (OS). Functional analyses, including gene ontology and pathway enrichment, were performed to elucidate the underlying biological mechanisms. RESULTS:ANGPT2 rs2959822 was significantly associated with PFS [hazard ratio (HR)=1.22, p=0.015] and OS (HR=1.22, p=0.021). The minor allele A increased the risk of disease progression and mortality. Functional analyses revealed that rs2959822 influenced ANGPT2 expression. Elevated ANGPT2 expression was correlated with higher Gleason score, advanced tumor stage, and shorter PFS. Gene set enrichment analysis linked ANGPT2 to epithelial-mesenchymal transition (EMT), demonstrating positive correlations with several key EMT genes, along with increased immune cell infiltration, indicating its multifaceted oncogenic roles. CONCLUSION:ANGPT2 rs2959822 influences the survival outcomes of patients with prostate cancer undergoing ADT. In addition to angiogenesis, ANGPT2 plays a critical role in prostate cancer progression by promoting EMT and modulating the tumor immune microenvironment.

Hypercrosslinked polymer (HCP) is a subclass of porous organic polymer possessing abundant microporosity, tailor-made functionality, and excellent stability. It features low-cost and easily direct knitting synthesis, facilitating the construction of π-conjugated frameworks with fluorescent properties by properly selecting building blocks (BBs) and linkers. Simultaneous imprinting of target molecules into the conjugated HCPs will create selective sorbents and sensors. We prepared several BBs to be polymerized with a terephthaloyl chloride (TCL) linker through Friedel–Crafts acylation in the presence of some imprinting molecules to clarify the best collocation for the advancement of imprinted polymer. With the highest increase in fluorescence intensity (F), the conjugated HCP comprised of dibenzofuran (DBF) and TCL was selected as contact with oxalic acid (OA). The OA-imprinted DBF-TCL (MICHP) was characterized by FTIR-approved structures, amorphous SEM images, TGA degradation at 390 °C, blue-shift emission, prolonged lifetime, and aggregation-caused quenching. The increase in F was proportional to OA concentration (0.17–20.0 μM, RSD = 1.6

One-carbon metabolism plays a crucial role in tumorigenesis as it supplies the one-carbon units necessary for nucleotide synthesis, epigenetic regulation, and redox metabolism, ensuring the rapid proliferation of cancer cells. However, their roles in prostate cancer progression remain poorly understood. In this study, we investigated the association between genetic variants in the one-carbon metabolism pathway and clinical outcomes in patients receiving androgen deprivation therapy for prostate cancer. The associations of 130 single-nucleotide polymorphisms located within 14 genes involved in the one-carbon metabolism pathway with cancer-specific survival (CSS), overall survival, and progression-free survival were assessed using Cox regression in 630 patients with prostate cancer. Subsequently, functional studies were performed using prostate cancer cell lines. After adjusting for covariates and multiple testing, MTHFD1L rs2073190 was found to be significantly associated with CSS (P = 0.000184). Further pooled analysis of multiple datasets demonstrated that MTHFD1L was upregulated in prostate cancer and increased MTHFD1L expression was positively correlated with tumor aggressiveness and poor patient prognosis. Functionally, MTHFD1L knockdown suppressed prostate cancer cell proliferation and colony formation. RNA sequencing and pathway analysis revealed that differentially expressed genes were predominantly enriched in the cell cycle pathway. In conclusion, genetic variants in MTHFD1L of one-carbon metabolism may serve as promising predictors, and our findings offer valuable insights into the underlying genetic mechanisms of prostate cancer progression.

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Renal cell carcinoma (RCC) is characterized by high mortality and morbidity rates. Vav guanine nucleotide exchange factors (VAVs), crucial for signal transduction between cell membrane receptors and intracellular mediators, have been implicated in carcinogenesis. However, their potential prognostic value in RCC remains unclear. The impact of 150 common VAV polymorphisms on RCC risk and survival was investigated in a cohort of 630 individuals. Publicly available gene expression datasets were utilized to analyze VAV gene expression in relation to patient outcomes. The VAV3 rs17019888 polymorphism was significantly associated with RCC risk and overall survival after adjusting for false discovery rates. Expression quantitative trait loci analysis revealed that the risk allele of rs17019888 is linked to reduced VAV3 expression. Analysis of 19 kidney cancer gene expression datasets revealed lower VAV3 expression in RCC tissues compared to normal tissues, with higher expression correlating with better prognosis. Gene set enrichment analysis demonstrated that VAV3 negatively regulates the ubiquitin-proteasome system, extracellular matrix and membrane receptors, inflammatory responses, matrix metalloproteinases, and cell cycle pathways. Furthermore, elevated VAV3 expression was associated with increased infiltration of B cells, macrophages, and neutrophils into the RCC tumor microenvironment. Our findings suggest that VAV3 gene variants influence RCC risk and survival, contributing to a favorable prognosis in RCC.

The skin of Arachis hypogaea L. (peanut or groundnut) is a rich source of polyphenols, which have been shown to exhibit a wider spectrum of noteworthy biological activities, including anticancer effects. However, the anticancer activity of peanut skin extracts against melanoma and colorectal cancer (CRC) cells remains elusive. In this study, we systematically investigated the cytotoxic, antiproliferative, pro-apoptotic, and anti-migration effects of peanut skin ethanolic extract and its fractions on melanoma and CRC cells. Cell viability results showed that the ethyl acetate fraction (AHE) of peanut skin ethanolic crude extract and one of the methanolic fractions (AHE-2) from ethyl acetate extraction exhibited the highest cytotoxicity against melanoma and CRC cells but not in nonmalignant human skin fibroblasts. AHE and AHE-2 effectively modulated the cell cycle-related proteins, including the suppression of cyclin-dependent kinase 4 (CDK4), cyclin-dependent kinase 6 (CDK6), phosphorylation of Retinoblastoma (p-Rb), E2F1, Cyclin A, and activation of tumor suppressor p53, which was associated with cell cycle arrest and paralleled their antiproliferative efficacies. AHE and AHE-2 could also induce caspase-dependent apoptosis and inhibit migration activities in melanoma and CRC cells. Moreover, it is noteworthy that autophagy, manifested by microtubule-associated protein light chain 3B (LC3B) conversion and the aggregation of GFP-LC3, was detected after AHE and AHE-2 treatment and provided protective responses in cancer cells. Significantly, inhibition of autophagy enhanced AHE- and AHE-2-induced cytotoxicity and apoptosis. Together, these findings not only elucidate the anticancer potential of peanut skin extracts against melanoma and CRC cells but also provide a new insight into autophagy implicated in peanut skin extracts-induced cancer cell death.

Background Treatment failure following androgen deprivation therapy (ADT) presents a significant challenge in the management of advanced prostate cancer. Thus, understanding the genetic factors influencing this process could facilitate the development of personalized treatments and innovative therapeutic strategies. The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway plays a pivotal role in controlling cell growth and tumorigenesis. We hypothesized that genetic variants within this pathway may affect the clinical outcomes of patients undergoing ADT for prostate cancer. Methods We genotyped 399 single-nucleotide polymorphisms (SNPs) across 28 core PI3K/AKT pathway genes in a cohort of 630 patients with prostate cancer undergoing ADT. We assessed the potential association of the SNPs with patient survival. Functional analyses of the implicated genes were also performed to evaluate their effects on prostate cancer. Results After multivariate Cox regression analysis and multiple testing correction, GABRB3 rs12591845 exhibited the most significant association with both overall and cancer-specific survivals ( P < 0.003). A comprehensive pooled analysis of 16 independent gene expression datasets revealed elevated expression of GABRB3 in prostate cancer tissues compared to that in normal tissues ( P < 0.001). Furthermore, gene set enrichment analysis unveiled differential enrichment of pathways such as myogenesis, interferon γ and α responses, and the MYC proto-oncogene pathway in tumors with elevated GABRB3 expression, implying a role for GABRB3 in prostate cancer. Conclusion Our results suggest that rs12591845 could potentially serve as a valuable prognostic indicator for patients undergoing ADT. The potential role of GABRB3 in promoting prostate tumorigenesis is also highlighted.