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PubMed2026

A PMS2-deficient pediatric high-grade glioma with PI3K-pathway mutations and adjacent developmental venous anomaly suggestive of CMMRD.

PURPOSE: Constitutional mismatch repair deficiency (CMMRD) is a rare hereditary cancer predisposition syndrome that frequently manifests with pediatric high-grade gliomas. However, recognition remains challenging, particularly in the absence of a clear family history. We report a pediatric high-grade glioma with PMS2 deficiency and complex molecular alterations to highlight key diagnostic clues and the importance of routine mismatch repair assessment. METHODS: Clinical, radiological, histopathological, immunohistochemical, and molecular findings of an 8-year-old girl presenting with a high-grade glioma were retrospectively evaluated. Immunohistochemistry included glial and mismatch repair markers. Targeted next-generation sequencing was performed to assess tumor mutational burden and pathogenic variants. RESULTS: Neuroimaging revealed a right frontoparietal mass associated with an adjacent developmental venous anomaly. Histopathology demonstrated a diffuse pediatric-type high-grade glioma with pseudopapillary architecture and marked mitotic activity. Immunohistochemistry showed diffuse p53 overexpression in tumor cells and complete loss of PMS2 expression in both tumor and non-neoplastic cells, supporting constitutional mismatch repair deficiency. Molecular analysis revealed an ultra-hypermutated profile with a tumor mutational burden of 117.4 mutations/Mb, a pathogenic PMS2 frameshift variant, and co-occurring alterations in TP53, PIK3CA, PIK3R1, and PTEN. The presence of PI3K-pathway mutations alongside a venous anomaly suggested a potential biological association. CONCLUSION: This case illustrates the characteristic clinicopathological and molecular features of CMMRD-associated pediatric high-grade glioma and underscores the critical role of routine mismatch repair immunohistochemistry. Integrated histological and genomic evaluation is essential for accurate diagnosis, appropriate genetic counseling, and potential therapeutic implications. Key Points • This case represents a pediatric high-grade glioma arising in the setting of PMS2-related constitutional mismatch repair deficiency (CMMRD). • The tumor exhibited an ultra-hypermutated profile with co-occurring TP53, PIK3CA, PIK3R1, and PTEN mutations. • Loss of PMS2 expression in both tumor and non-neoplastic cells was critical in establishing the diagnosis of CMMRD. • The presence of a developmental venous anomaly may relate to underlying PIK3R1 pathway alterations. • Routine mismatch repair immunohistochemistry is essential in pediatric high-grade gliomas, even in the absence of a family history.

Humans↗

PubMed2024

Polycystic ovarian syndrome (PCOS) and recurrent spontaneous abortion (RSA) are associated with the PI3K-AKT pathway activation.

AIMS: We aimed to elucidate the mechanism leading to polycystic ovarian syndrome (PCOS) and recurrent spontaneous abortion (RSA). BACKGROUND: PCOS is an endocrine disorder. Patients with RSA also have a high incidence rate of PCOS, implying that PCOS and RSA may share the same pathological mechanism. OBJECTIVE: The single-cell RNA-seq datasets of PCOS (GSE168404 and GSE193123) and RSA GSE113790 and GSE178535) were downloaded from the Gene Expression Omnibus (GEO) database. METHODS: Datasets of PSCO and RSA patients were retrieved from the Gene Expression Omnibus (GEO) database. The "WGCNA" package was used to determine the module eigengenes associated with the PCOS and RSA phenotypes and the gene functions were analyzed using the "DAVID" database. The GSEA analysis was performed in "clusterProfiler" package, and key genes in the activated pathways were identified using the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Real-time quantitative PCR (RT-qPCR) was conducted to determine the mRNA level. Cell viability and apoptosis were measured by cell counting kit-8 (CCK-8) and flow cytometry, respectively. RESULTS: The modules related to PCOS and RSA were sectioned by weighted gene co-expression network analysis (WGCNA) and positive correlation modules of PCOS and RSA were all enriched in angiogenesis and Wnt pathways. The GSEA further revealed that these biological processes of angiogenesis, Wnt and regulation of cell cycle were significantly positively correlated with the PCOS and RSA phenotypes. The intersection of the positive correlation modules of PCOS and RSA contained 80 key genes, which were mainly enriched in kinase-related signal pathways and were significant high-expressed in the disease samples. Subsequently, visualization of these genes including PDGFC, GHR, PRLR and ITGA3 showed that these genes were associated with the PI3K-AKT signal pathway. Moreover, the experimental results showed that PRLR had a higher expression in KGN cells, and that knocking PRLR down suppressed cell viability and promoted apoptosis of KGN cells. CONCLUSION: This study revealed the common pathological mechanisms between PCOS and RSA and explored the role of the PI3K-AKT signaling pathway in the two diseases, providing a new direction for the clinical treatment of PCOS and RSA.

Humans↗

PubMed2026

Diosmetin Inhibits Bladder Cancer through Suppression of the PI3K-AKT Signaling Pathway and Activation of the p53 Signal Pathway Revealed by Network Pharmacology and In Vitro Experimental Verification.

INTRODUCTION: Diosmetin, a naturally occurring flavonoid abundant in plants such as chrysanthemums, lemons, and oranges, has been reported to exhibit diverse antitumor properties. However, its potential efficacy against bladder cancer remains unexplored. This study aims to investigate the anti-bladder cancer effects of Diosmetin and elucidate the underlying mechanisms using network pharmacology combined with in vitro experiments. METHODS: Public databases were employed to identify shared targets between Diosmetin and bladder cancer. A Protein-Protein Interaction (PPI) network was constructed, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses to predict core targets and signaling pathways. The predicted mechanisms were subsequently validated through in vitro assays. RESULTS: A total of 48 common targets were identified. PPI network analysis revealed 22 hub genes, including AKT1 and MDM2. GO analysis indicated enrichment in 208 biological processes, 23 cellular components, and 38 molecular functions. KEGG analysis suggested that Diosmetin exerts anti-bladder cancer effects primarily through pathways such as Pathways in cancer, PI3K-AKT signaling, and Proteoglycans in cancer. Notably, the PI3K-AKT pathway showed the highest gene enrichment, indicating its potential prominence. In vitro experiments demonstrated that Diosmetin suppresses bladder cancer cell proliferation and induces apoptosis. Additionally, Diosmetin reduced the expression of p-PI3K, p-AKT, and MDM2, while upregulating p53 expression, suggesting involvement of both the PI3K-AKT and p53 pathways. DISCUSSION: These findings align with network pharmacology predictions and highlight the potential of Diosmetin as a multi-target agent against bladder cancer, warranting further in vivo investigation. CONCLUSION: Diosmetin inhibits bladder cancer cell proliferation and promotes apoptosis by suppressing the PI3K-AKT pathway and activating the p53 pathway.

Diosmetin↗

PubMed2026

Phase 1 trial and biomarker analysis of Buparlisib with weekly Cisplatin and Radiotherapy in high risk locally advanced squamous cell cancer of the Head and Neck.

PURPOSE: We evaluated the pan-PI3K inhibitor buparlisib with weekly cisplatin and radiotherapy among patients with locally advanced (LA) squamous cell cancer of the head and neck (SCCHN) and tobacco history. PATIENTS AND METHODS: Patients with stage III/IV LA-SCCHN (AJCC7), ≥10 pack-year tobacco use treated with curative intent were enrolled. Patients received buparlisib during a 2-week run-in phase and during standard 70Gy of radiotherapy plus weekly cisplatin. An exploratory analysis of genomic sequencing was performed on biopsy specimens Results: Twenty-three patients were enrolled (n=17 at the MTD (buparlisib 40 mg daily, CDDP 30mg/m2/week)). Ninety-one percent (21/23) had stage IV disease. HPV was detected in 15 of 18 cases with oral/oropharyngeal disease. 5 patients suffered recurrences of whom 3 had activating mutations along the PI3K pathway. In 5 patients whose disease responded during the 2 week run-in phase with buparlisib alone, 3 of 4 with sequencing data showed loss-of-function mutations in either Tumor Necrosis Factor Receptor Associated Factor 3 (TRAF3), and/or Cylindromatosis Lysine Deubiquinatinase (CYLD). Preclinical studies with mutations in TRAF3 or CYLD via CRISPR/Cas9 knockout in HPV+SCCHN cells demonstrate that loss of TRAF3 or CYLD may sensitize SCCHN cell lines to PI3K through mechanisms other than blocking NFκb pathway. CONCLUSIONS: Buparlisib with CRT was feasible and active, though escalation to the standard weekly cisplatin dose of 40 mg/m2 was not possible. Our data suggests that TRAF3/CYLD mutant SCCHN may be susceptible to PI3K inhibition whereas PI3K pathway activation appeared to be associated with poor outcomes in this limited dataset.

Journal Article↗

PubMed2026

PIK3CA in Cancer: Structure, Biology, Alterations, and Actionability.

PIK3CA, which encodes the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K), is one of the most frequently altered oncogenes in human cancer and a major driver of tumor initiation, progression, metastasis, and therapeutic resistance. Over the past two decades, advances in structural biology, cancer genomics, and translational research have substantially expanded our understanding of PIK3CA function and established the PI3K pathway as a clinically actionable therapeutic target. This review provides an overview of the structural organization and physiological functions of the PI3Kα complex, the molecular mechanisms underlying oncogenic activation, and the diverse spectrum of PIK3CA alterations across human malignancies. We also summarize the current landscape of PI3K-targeted therapies, highlighting both approved agents and emerging therapeutic strategies. Clinical evidence supports the rational integration of PI3K inhibitors with endocrine therapy, CDK4/6 inhibitors, MAPK pathway inhibitors, dual PI3K/mTOR inhibition, and immune checkpoint blockade. In addition, accumulating evidence indicates that PIK3CA plays a pivotal role in shaping the tumor immune microenvironment, providing a biological rationale for combining PI3K inhibition with immunotherapy. Finally, we discuss future directions in precision oncology, emphasizing integrated molecular profiling, liquid biopsy, single-cell and spatial technologies, functional genomics, and evolutionary approaches as complementary strategies to refine patient selection, overcome therapeutic resistance, and optimize clinical outcomes.

PI3K signaling↗

PubMed2026

Landscape of genetic alterations affecting cancer genes in primary and advanced malignant phyllodes tumours.

BACKGROUND: Malignant phyllodes tumours (MPT) are aggressive breast fibroepithelial neoplasms. Their rarity has limited their genetic characterization, and associations with genetic ancestry and progression drivers remain poorly understood. Prior studies suggest two evolutionary pathways according to MED12 mutational status. We sought to determine the repertoire of somatic genetic alterations in cancer genes in primary versus metastatic/recurrent MPTs, and according to MED12 mutational status and genetic ancestry. MATERIALS AND METHODS: We analysed the paired tumour-normal targeting sequencing data (up to 505 cancer-related genes) of 31 MPTs (primary, n = 20; metastatic/recurrent, n = 11). RESULTS: Metastatic/recurrent MPTs harboured a numerically higher frequency of genetic alterations in CDKN2A/2B (55% vs. 25%). Moreover, analysis of an MPT case with paired primary and metastatic samples revealed a CDKN2A/2B homozygous deletion restricted to the metastatic sample, suggesting a role for CDKN2A/2B in progression. Compared with MED12-wild type MPTs, MED12-mutant MPTs had higher tumour mutation burden (P = 0.002), frequency of TERT promoter (82% vs. 35%; P = 0.02) and RB1 mutations (45% vs. 5%; P = 0.01). Genetic alterations in the PI3K pathway, including PIK3CA and PTEN, were only present in MED12-wild type MPTs, and absent in MED12-mutant cases (15% vs. 0%; P > 0.05). Furthermore, genetic alterations in EGFR were restricted to MPTs from patients of European genetic ancestry and absent in those of Asian ancestry (43% vs. 0%; P > 0.05). CONCLUSIONS: Taken together, the repertoire of genetic alterations in primary and metastatic/recurrent MPTs shows overlap, and CDKN2A/2B homozygous deletions may play a role in progression. Additionally, molecular profiles of MPTs may vary according to genetic ancestry and MED12 mutational status.

Humans↗

PubMed2026

A novel lactylation-related gene signature deciphers the immunosuppressive microenvironment and stratifies precision therapy in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) remains a leading cause of cancer mortality, largely due to the heterogeneity of the tumor microenvironment (TME) and the limited efficacy of immunotherapy in microsatellite stable (MSS) tumors. Histone lactylation, a post-translational modification derived from the Warburg effect, serves as a critical bridge linking metabolic reprogramming to gene regulation and immune evasion; however, its specific prognostic value and clinical implications in CRC remain to be fully elucidated. METHODS: In this study, we systematically analyzed transcriptome profiling data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts, supplemented by single-cell RNA sequencing (scRNA-seq) analysis and Human Protein Atlas (HPA) protein-level validation. By integrating univariate Cox regression, Least Absolute Shrinkage and Selection Operator (LASSO) analysis, and multivariate Cox regression, we constructed a novel lactylation-related gene (LRG) risk signature. We extensively evaluated the association between this risk signature and patient prognosis, immune infiltration patterns, somatic mutations, and therapeutic sensitivity. RESULTS: A robust 9-gene prognostic signature (DHRS7, SPR, MBD2, RBM17, CSRP2, S100A4, TMSB4X, TKT, COPS4) was identified and corroborated at the protein level. Patients with high risk scores exhibited significantly worse overall survival (OS) across the training and two independent validation cohorts. Immunogenomic and scRNA-seq analyses revealed that high-risk tumors were characterized by an immunosuppressive and stromal-dense microenvironment-with stromal cells exhibiting the highest lactylation risk scores-enriched with regulatory T cells (Tregs), and frequently harbored PIK3CA mutations. Differential expression analysis indicated that this immune exclusion is structurally maintained by enriched extracellular matrix (ECM) organization and TGF-β signaling. Conversely, low-risk tumors displayed an inflamed phenotype with active antitumor immunity. Pharmacogenomic prediction identified distinct therapeutic stratifications: low-risk patients exhibited significant sensitivity to standard chemotherapeutics (fluorouracil, oxaliplatin) and EGFR/HER2 inhibitors (e.g., lapatinib, erlotinib). In contrast, high-risk patients showed specific vulnerabilities to novel targeted agents, including PI3K pathway inhibitors (TG-100-115, XL765), microenvironment-modulating agents (sildenafil, GANT-61), and epigenetic inhibitors (UNC0638). CONCLUSION: We established a novel lactylation-related risk signature that effectively stratifies CRC patients by prognosis and TME characteristics. By elucidating the crosstalk between metabolic dysregulation, stromal barriers, and immune exclusion, this study provides potential biomarkers and stratified therapeutic strategies-ranging from standard chemotherapy to targeted metabolic and stromal interventions-to optimize precision medicine for CRC patients.

Colorectal cancer↗

PubMed2026

Hypoxia reprograms VEGF signaling to differentially control ADAMTS2 and ADAMTS3 expression in endothelial cells.

ADAMTS2/-3, key metalloproteinases involved in collagen processing and extracellular matrix dynamics, remain insufficiently characterized in terms of their transcriptional regulation under hypoxic and pro-angiogenic conditions. In this study, we demonstrate that VEGF₁₆₅ robustly enhances ADAMTS2/-3 expression in endothelial cells, with hypoxia providing a striking amplification of this response. Bioinformatic analyses revealed that hypoxia and VEGF induced HIF-mediated and time-varying expression responses in ADAMTS2/-3. Using HUVECs exposed to CoCl₂-induced hypoxia, VEGF stimulation led to substantial increases in ADAMTS2 (approximately 19-fold at 3 h) and ADAMTS3 (approximately 46-fold at 3 h) mRNA levels, accompanied by concordant protein upregulation. Promoter-reporter assays revealed strong VEGF responsiveness in defined ADAMTS2 (-658/+112) and ADAMTS3 (-131/+40; -1340/+40) promoter fragments, particularly under hypoxic conditions. Pharmacological inhibition showed that JNK, MAPK/ERK, p38, and PI3K pathways each contributed partially to VEGF-mediated transcription, indicating multi-pathway convergence rather than single-pathway dependency. This finding is consistent with RNA-seq analyses showing that VEGF-related signaling is extensively re-regulated under hypoxic conditions. Extension of these analyses to MG-63 and SAOS-2 cell lines revealed modest but consistent VEGF-induced upregulation, supporting a tissue-independent regulatory axis. Collectively, these findings position ADAMTS2/-3 as potent hypoxia- and VEGF-responsive genes, uncovering their integration into HIF-1α-dependent transcriptional networks and VEGF-activated signaling cascades. This work highlights the relevance of ADAMTS2/-3 in angiogenesis-associated extracellular matrix remodeling and identifies them as promising biomarkers and potential therapeutic targets in hypoxia-driven vascular pathology.

Humans↗

PubMed2026

Multi-sampling allows intra-tumoral heterogeneity querying and vulnerability profiling in glioblastoma.

BACKGROUND: Glioblastoma (GBM) remains a devastating cancer with limited treatment options, largely due to its heterogeneity. While supramaximal resection has recently provided survival benefits, therapeutic profiling of different tumor compartments, particularly its infiltrative edge remains largely unexplored. METHODS: Here, we leveraged magnetic resonance imaging (MRI)-guided multi-sampling, collecting 2 cores and 2 margins per case, to query GBM heterogeneity. Whole-exome and RNA-seq with drug testing in two patient-derived 3D models were used to reveal similarities and differences in genomic and transcriptomic makeups, cellular compositions, and drug responses across cores and margins. Bioinformatics interrogations further identified response biomarkers. RESULTS: Mutation analysis showed that oncogenes exhibited a higher degree of spatial heterogeneity than tumor suppressor genes, regardless of MRI status. While the mesenchymal transcriptional subtype with extracellular matrix remodeling, stress response, and immune programs were preferentially enriched in enhancing cores, proneural tumors with neurological processes favored non-enhancing margins. Using a 15-drug GBM-targeted panel, ERK (ulixertinib) and PI3K pathway (paxalisib, CC-115) inhibitors showed preferential efficacy in enhancing cores and non-enhancing margins, respectively. The anti-apoptosis, pan-Bcl2 agent navitoclax and the epigenetic drug trotabresib represented the most effective, tumor-wide monotherapies. Importantly, drug combinations generally outperformed single agents across all regions. CONCLUSIONS: This work demonstrates the regional heterogeneity of therapeutic vulnerabilities in GBM ex vivo, showing various drugs with tumor-wide or MRI-enhancement informed activity. These findings offer preclinical bases of numerous monotherapies and drug combinations for future clinical trial design.

Humans↗

PubMed2026

Genomic Profiling of Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer after Progression on First-line Osimertinib: Phase II ORCHARD Study.

PURPOSE: Osimertinib is the standard of care for first-line treatment for epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC). Understanding the tumor molecular profile of patients following progression on osimertinib could help inform optimal second-line treatment. PATIENTS AND METHODS: ORCHARD (NCT03944772), a phase II biomarker-directed study, enrolled patients with EGFRm NSCLC who progressed on first-line osimertinib to receive treatment based on their tumor molecular profile after progression. The study comprised three groups into which patients were allocated based on the molecular profile of their tumor, determined via next-generation sequencing (NGS) of a tumor biopsy. We report results from a prespecified, exploratory analysis of baseline tumor tissue and plasma samples to evaluate mechanisms of resistance to first-line osimertinib identified by tissue and plasma NGS. Agreement between tissue and plasma NGS data was also assessed. RESULTS: This study provided a comprehensive dataset exploring tissue (n = 400) and plasma (n = 191) genomics, enabling characterization of the histogenomic landscape after first-line osimertinib treatment. TP53 and MDM2/4 alterations were mutually exclusive and occurred in 86% of tumors. When combining tissue and plasma genomics, resistance alterations were detected in 87% of samples, with multiple resistance alterations in 46%. Alterations in the PI3K pathway, SOX2, and MYC were frequently detected in histologically transformed tumors. Additionally, differential patterns of co-occurring EGFR mutations in tumors with L858R versus exon 19 deletion were observed. CONCLUSIONS: This comprehensive analysis highlights potential heterogeneous resistance to first-line osimertinib treatment, providing a rationale for combining treatments with broad activity to improve patient outcomes. See related commentary by Gupta et al., p. 3718.

Humans↗

PubMed2026

High tumor mutational burden and PIK3CA mutations correlate with poor Merkel cell carcinoma-specific survival.

Merkel cell carcinoma (MCC) is a neuroendocrine carcinoma of the skin characterized by poor prognosis. This study aimed to explore the relationship between genetic alterations, tumor mutational burden (TMB), and MCC-specific survival (MCC-SS) in patients who underwent genomic profiling of tumors with OncoPanel. Univariate and multivariable analysis were used to assess the impact of genetic alterations on MCC-SS. Of the 188 identified patients, 164 were included in the analysis. The cohort had a mean age of 72.4 years (SD = 11.03), including 61.6% male. The median TMB was 5.32 (IQR = 3.04-25.53). Kaplan-Meier curves by high versus low TMB were significantly different (log-rank test, P = 0.017). PIK3CA (adjusted P = 0.003), SETBP1 (adjusted P = 0.002), KDR (adjusted P = 0.028), and RET (adjusted P = 0.033) were selected for multivariable analysis. In the multivariable regressions, only PIK3CA (HR = 2.07 [95% CI, 1.10-3.88]; P = 0.024) remained significant. PIK3CA remained significant across prespecified sensitivity analyses. In this study, high TMB and PIK3CA alterations were associated with poor MCC-SS. Identifying a higher-risk subgroup may inform risk stratification and motivate further evaluation of PI3K pathway targeting in future studies.

Humans↗

PubMed2026

METTL14-mediated m6A modification of CCNE1 accelerates progression of myelodysplastic syndromes via MAPK-ERK and PI3K-AKT signaling pathways.

BACKGROUND: N6-methyladenosine (m6A) is the most common RNA modification and plays a key role in the initiation, progression, and relapse of multiple cancers, including hematologic malignancies. However, the role of m6A and m6A regulatory genes in myelodysplastic syndromes (MDS) remains unclear. This study aims to elucidate the function and molecular mechanism of methyltransferase METTL14 in MDS. METHODS: RT-qPCR was used to assess the expression of multiple m6A regulators, focusing on METTL14 in MDS patients and cell lines. METTL14 overexpressing and knockdown cell lines were established, and CCK-8, EdU, and flow cytometry assays were performed to explore the biological functions of METTL14.Dot blot, MeRIP-Seq, MeRIP-qPCR, RT-qPCR, and Western blot were employed to investigate the underlying molecular mechanism. RESULTS: Dysregulation of multiple m6A regulators was observed in MDS, among which METTL14 was upregulated. Elevated METTL14 expression increases MDS risk and adverse prognosis, emerging as a biomarker for poor prognosis. METTL14 promoted proliferation and cell-cycle progression of MDS cells while inhibiting apoptosis; corresponding changes were observed in cell cycle and apoptosis markers. METTL14 regulated cellular m6A levels. Downstream targets of METTL14 were enriched in cell cycle-related pathways, with CCNE1 identified as a critical target. Knockdown of METTL14, actinomycin D, or S-adenosylhomocysteine treatment reduced CCNE1 mRNA and protein levels. Furthermore, METTL14 activated MAPK-ERK and PI3K-AKT signaling via CCNE1 in an m6A-dependent manner, thereby promoting proliferative MDS cells' capacity. CONCLUSIONS: This study delineates a METTL14/m6A/CCNE1 signaling axis in MDS progression and suggests that METTL14-mediated m6A modification may be a potential therapeutic target for MDS.

Humans↗

PubMed2025

Molecular alterations in TP53, WNT, PI3K, TGF-Beta and RTK/RAS pathways in gastric cancer among ethnically heterogeneous cohorts.

BACKGROUND/OBJECTIVES: Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with significant racial and ethnic disparities in incidence, molecular characteristics, and patient outcomes. However, genomic studies focusing on Hispanic/Latino (H/L) populations remain scarce, limiting our understanding of ethnicity-specific molecular alterations. This study aims to characterize pathway-specific mutations in TP53, WNT, PI3K, TGF-Beta and RTK/RAS signaling pathways in GC and compare mutation frequencies between H/L and Non-Hispanic White (NHW) patients. Additionally, we evaluate the impact of these alterations on overall survival using publicly available datasets. METHODS: We conducted a bioinformatics analysis using publicly available GC datasets to assess mutation frequencies in TP53, WNT, PI3K, TGF-Beta and RTK/RAS pathway genes. A total of 800 patients were included in the analysis, comprising 83 H/L patients and 717 NHW patients. Patients were stratified by ethnicity (H/L vs. NHW) to evaluate differences in mutation prevalence. Chi-squared tests were performed to compare mutation rates between groups, and Kaplan-Meier survival analysis was used to assess overall survival differences based on pathway alterations among both H/L and NHW patients. RESULTS: Significant differences were observed in the TP53 pathway and related genes when comparing GC in H/L patients to NHW patients. TP53 mutations were less prevalent in H/L patients (9.6% vs. 19%, p = 0.03). Borderline significant differences were noted in the WNT pathway when comparing GC in H/L patients to NHW GC patients, with WNT alterations more frequent in H/L GC (8.4% vs. 4%, p = 0.08), and APC mutations significantly higher (3.6% vs. 0.8%, p = 0.05). Although alterations in PI3K, TGF-Beta and RTK/RAS pathways were not statistically significant, borderline significance was observed in genes related to these pathways, including EGFR (p = 0.07), FGFR1 (p = 0.05), FGFR2 (p = 0.05), and PTPN11 (p = 0.05) in the PI3K pathway, and SMAD4 (p = 0.08) in the TGF-Beta pathway. Survival analysis revealed no significant differences among H/L patients. However, NHW patients with TP53 and PI3K pathway alterations exhibited significant differences in overall survival, while those without TGF-Beta pathway alterations also showed a significant survival impact. In contrast, WNT pathway alterations were not associated with significant survival differences. These findings suggest that TP53, PI3K, and TGF-Beta pathway disruptions may have distinct prognostic implications in NHW GC patients. CONCLUSIONS: This study provides one of the first ethnicity-focused analyses of TP53, WNT, PI3K, TGF-Beta and RTK/RAS pathway alterations in GC, revealing significant racial/ethnic differences in pathway dysregulation. The findings suggest that TP53 and WNT alterations may play a critical role in GC among H/L patients, while PI3K and TGF-Beta alterations may have greater prognostic significance in NHW patients. These insights emphasize the need for precision medicine approaches that account for genetic heterogeneity and ethnicity-specific pathway alterations to improve cancer care and outcomes for underrepresented populations.

PI3K pathway↗

PubMed2001

Regulation of thyroid cell proliferation by TSH and other factors: a critical evaluation of in vitro models.

TSH via cAMP, and various growth factors, in cooperation with insulin or IGF-I stimulate cell cycle progression and proliferation in various thyrocyte culture systems, including rat thyroid cell lines (FRTL-5, WRT, PC Cl3) and primary cultures of rat, dog, sheep and human thyroid. The available data on cell signaling cascades, cell cycle kinetics, and cell cycle-regulatory proteins are thoroughly and critically reviewed in these experimental systems. In most FRTL-5 cells, TSH (cAMP) merely acts as a priming/competence factor amplifying PI3K and MAPK pathway activation and DNA synthesis elicited by insulin/IGF-I. In WRT cells, TSH and insulin/IGF-I can independently activate Ras and PI3K pathways and DNA synthesis. In dog thyroid primary cultures, TSH (cAMP) does not activate Ras and PI3K, and cAMP must be continuously elevated by TSH to directly control the progression through G(1) phase. This effect is exerted, at least in part, via the cAMP-dependent activation of the required cyclin D3, itself synthesized in response to insulin/IGF-I. This and other discrepancies show that the mechanistic logics of cell cycle stimulation by cAMP profoundly diverge in these different in vitro models of the same cell. Therefore, although these different thyrocyte systems constitute interesting models of the wide diversity of possible mechanisms of cAMP-dependent proliferation in various cell types, extrapolation of in vitro mechanistic data to TSH-dependent goitrogenesis in man can only be accepted in the cases where independent validation is provided.

Animals↗

PubMed2026

AKR7A3 rs1738023 association with susceptibility to female hepatocellular carcinoma and its role in AFB1 metabolism and tumor.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common cancer worldwide. In this study, we performed a two-stage exome-chip association analysis and found that the aldo-keto reductase family7 member A3 (AKR7A3) rs1738023 may be a potential susceptibility locus for HCC in females. We aimed to explore its role and mechanism. METHODS: The association between genotype and phenotype was analyzed through GWAS method. The expression of AKR7A3 in cancer tissue and blood analysis by qRT-PCR. The relationship of AKR7A3 and aflatoxin B1 (AFB1) was also analyzed. The effect of AKR7A3 on the biological behavior of HCC cell line was investigated on proliferation and invasion. The potential mechanism was analyzed by transcriptome analysis and western blot. RESULTS: Through genome-wide association analysis (GWAS), AKR7A3 (rs1738023), KIF2C (rs4342887), and CYP3A5 (rs6977165 and rs4646450) were found to be associated with susceptibility to hepatocellular carcinoma (HCC) in women. Further expression quantitative trait loci (eQTL) analysis showed that only AKR7A3 (rs1738023) was significantly associated with gene expression. The expression of AKR7A3 was significantly lower in HCC than adjacent non-tumorous tissues (P < 0.001). The genotype of rs1738023 was significantly associated with AKR7A3 expression (P = 0.0085). Rs1738023[C] genotype had a low AKR7A3 expression level and limited detoxification ability of AFB1. Literature data showed that AKR7A3 is involved in the metabolism of aflatoxin B1 (AFB1). Functional experimental results showed that overexpression of AKR7A3 in the normal liver cell line HL-7702 could significantly reduce AFB1-induced ROS levels and DNA adduct formation, suggesting that it plays a protective role in AFB1 metabolic detoxification. Cell function test showed that overexpression of AKR7A3 inhibit the proliferation, migration and invasion of HCC cells, and block the cell cycle. Transcriptome sequencing and KEGG pathway enrichment analysis revealed that overexpression of AKR7A3 affected the PI3K signaling pathway and led to downregulation of HIF1A and its downstream VEGFA protein expression. The validation results were confirmed in HCC cell lines Huh-7 and SUN-387. CONCLUSION: Overexpression of AKR7A3 contributes to inhibition of HCC progression and reduction of aflatoxin toxicity. AKR7A3 may serve as a potential prognostic and therapeutic target for HCC patients, although further validation is needed.

AKR7A3↗

PubMed2025

Exploration of the mechanism of the Mongolian medicine Tonglaga-5 (-5) for the treatment of n-methyl-n'-nitro-n-nitrosoguanidine-induced chronic atrophic gastritis based on network pharmacology and metabolomics.

OBJECTIVE: To explore the mechanism of Tonglaga-5 (-5, TLG-5) for the treatment of chronic atrophic gastritis (CAG), based on network pharmacology and metabolomics. METHODS: Forty-eight male Sprague-Dawley rats were randomly divided into six groups (n = 8): control group; model group; teprenone group, and low-, median-, and high- dose TLG-5 groups. The enzyme linked immunosorbent assay (ELISA) was used to measure the expression of pepsinogen Ⅰ (PG Ⅰ), pepsinogen Ⅱ (PG Ⅱ) and gastrin-17 (G-17) in the serum. Hematoxylin and eosin staining were performed to observe the pathological condition. And the network pharmacology was employed to identify the targets and signaling pathways of TLG-5 affecting CAG. Then, the metabolomics approach was applied to explore the specific metabolites and metabolic pathways. Finally, validation was performed using the "metabolite-gene" interaction network, molecular docking and quantitative real-time polymerase chain reaction (qPCR). RESULTS: High-dose TLG-5 significantly improved the expression of PG Ⅰ, PGR (PG Ⅰ/ PG Ⅱ) and G-17 (P < 0.05) and inhibited the expression of phosphoinositide-3-kinase regulatory subunit 2, AKT serine/threonine kinase (AKT), hypoxia-inducible factor 1-alpha (HIF-1α) (P < 0.05). Further, high-dose TLG-5 reduced the number of glands was reduced, and fibrosis with oedema and ecchymosis appeared at the base. Overlapping TLG-5 and CAG gene targets produced 270 interactive targets. The results of gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses suggested that TLG-5 could affect CAG through the predominantly cancer and inflammation-related pathways. Pyrimidine metabolism was identified as a significantly differential pathway in the mechanism of TLG-5 for treating CAG. CONCLUSIONS: TLG-5 exerts a therapeutic effect on CAG by regulating β-alanine metabolism, pyrimidine metabolism pathways, and inhibiting the PI3K-AKT signaling pathway and HIF-1 signaling pathways.

Animals↗

PubMed2026

Crosstalk between the Wnt pathway and other signaling pathways.

The Wnt/β-catenin signaling pathway is a deeply conserved regulatory network that governs embryonic development, stem cell maintenance, and tissue homeostasis. Aberrant activation of the Wingless/Integrated protein (Wnt) signaling is a hallmark of numerous human diseases, most prominently in colorectal cancer, where it cooperates with additional oncogenic pathways to drive tumor initiation, progression, and therapeutic resistance (See Supplementary Table 1 for a list of the abbreviations used in this manuscript and their definitions.). Increasing evidence indicates that Wnt signaling does not function as an isolated linear cascade but rather as an integrative signaling hub that dynamically interfaces with major signaling pathways, including the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways. Rat Sarcoma protein (RAS)- Rapidly Accelerated Fibrosarcoma protein (RAF)- Mitogen-Activated Protein Kinase (MAPK) and Phosphoinositide 3-Kinase (PI3K)- Ak strain transforming protein (AKT)- Mechanistic Target of Rapamycin (mTOR) pathways. These interactions occur at multiple molecular levels, encompassing shared kinases, transcriptional regulators, metabolic nodes, and cytoskeletal components, thereby coordinating proliferative, metabolic, and migratory programs. In this review, we synthesize current mechanistic and clinical insights into the crosstalk between Wnt signaling and the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways, with particular emphasis on colorectal cancer. We discuss how these signaling networks converge to regulate β-catenin stability, transcriptional activity, cell adhesion, and metabolic reprogramming, thereby generating oncogenic phenotypes that cannot be explained by activation of individual pathways alone. To illustrate the evolutionary conservation and biological significance of these interactions, we integrate developmental paradigms from early Xenopus embryogenesis, where Wnt signaling governs zygotic genome activation, body axis formation, and the regulation of cell growth, protein stability, and biomass accumulation. Finally, we examine how an improved understanding of Wnt-centered signaling networks is informing emerging therapeutic strategies, including combinatorial pathway inhibition and nanoparticle-based drug delivery. Collectively, this review highlights Wnt signaling as a central integrator of developmental and oncogenic programs, providing a conceptual framework for understanding signaling network crosstalk and identifying new therapeutic opportunities in cancer.

Humans↗

PubMed2025

The Involvement of PI3K-Akt Signaling in the Clinical and Pathological Findings of Idiopathic Multicentric Castleman Disease-Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis, and Organomegaly and Not Otherwise Specified Subtypes.

Idiopathic multicentric Castleman disease is a rare lymphoproliferative disorder that is clinically classified into idiopathic plasmacytic lymphadenopathy (IPL); thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO); and not otherwise specified (NOS). Although each subtype shows varying degrees of hypervascularity, no statistical data on the degree of vascularization have been reported. Additionally, the mechanisms underlying vascularization in each clinical subtype are poorly understood. Here, we aimed to clarify these mechanisms by evaluating the histopathological characteristics of each clinical subtype across 37 patients and performing a whole-transcriptome analysis focusing on angiogenesis-related gene expression. Histologically, TAFRO and NOS exhibited a significantly higher degree of vascularization than IPL (IPL vs TAFRO, P < .001; IPL vs NOS, P = .002). In addition, the germinal centers (GCs) were significantly more atrophic in TAFRO than in IPL. In TAFRO and NOS, "whirlpool vessels" in GCs were seen in most cases (TAFRO, 9/9, 100%; NOS, 6/8, 75%) but not in IPL (IPL vs TAFRO, P < .001; IPL vs NOS, P = .007). Likewise, immunostaining for Ets-related gene revealed higher levels in endothelial cells of GCs in TAFRO than in IPL (P = .014), and TAFRO and NOS were associated with a significantly higher number of endothelial cells in interfollicular areas compared with that in IPL (TAFRO vs IPL, P < .001; NOS vs IPL, P = .002). Gene expression analysis revealed that the PI3K-Akt signaling pathway was significantly enriched in the TAFRO and NOS (TAFRO/NOS) groups. This pathway, which may be activated by vascular endothelial growth factor A and some integrins, is known to affect angiogenesis by increasing vascular permeability, which may explain the clinical manifestations of anasarca and/or fluid retention in TAFRO/NOS. These results suggest that the PI3K-Akt pathway plays an important role in the pathogenesis of TAFRO/NOS.

Humans↗