The interplay between TP53 alterations and Wnt/β-catenin signaling in colorectal cancer (CRC) remains unclear regarding mismatch repair (MMR) status, tumor budding (TB), poorly differentiated cluster (PDC), and prognosis. We analyzed 146 resected CRC cases, quantifying p53, Wnt3, and β-CTN indices and assessing MMR by PMS2 and MSH6 immunohistochemistry. p53 overexpression was associated with younger patients, left-sided tumors, nodal metastasis, and advanced stage, whereas wild-type tumors showed more mucinous differentiation. Deficient MMR was enriched among wild-type p53 cases. Principal component analysis identified distinct axes defined by p53, Wnt3, and β-CTN. Despite comparable Wnt3 levels, nuclear β-CTN accumulation was enhanced in tumors with aberrant (overexpression or null) p53 tumors, with increased TB and PDC indices. Low nuclear β-CTN independently predicted recurrence in stage I-III disease and worse overall survival in proficient MMR tumors (HR 3.07 and 2.52; p = 0.03 for both). A composite score integrating p53 binary status (aberrant vs. wild) with Wnt3 and whole β-CTN indices predicted survival beyond stage; each 1-point increase conferred a 2.56- and 1.77-fold higher risk of cancer-specific and overall mortality (p = 0.004 and 0.04). These findings suggest that p53 dysfunction is associated with alterations in Wnt/β-CTN signaling and that integrating signaling markers with staging may improve prognostic assessment in colorectal cancer.

From an epidemiological perspective, polymorphous low-grade neuroepithelial tumor (PLNTY) represents a small proportion of brain tumors encountered in epilepsy surgery series. Their rarity and relatively recent recognition likely contribute to underdiagnosis and poor prognosis. In terms of histopathological features, they are similar to oligodendrogliomas. Molecular analyses can be used to show the fusion between fibroblast growth factor receptor (FGFR3) and transforming acidic coiled coil (TACC) proteins, which most commonly results in progression towards glioblastoma (GBM). We report a case of a 62-year-old man who underwent left frontal craniotomy to remove a frontal mass. Histologically, the glial lesion consisted of elements associated with oligodendroglia-like features. Immunohistochemistry was positive for glial fibrillary acidic protein (GFAP), oligodendrocyte transcription factor 2 (OLIG2), and α-thalassemia X-linked mental retardation syndrome (ATRX) nuclear expression, but negative for isocitrate dehydrogenase 1 (IDH1) and BRAF-V600E. Next-generation sequencing showed the FGFR-TACC3 fusion, and taken together, these findings supported the final diagnosis of PLNTY. During follow-up, the patient underwent a second neurosurgery, where histological evaluation indicated a GMB. This article presents clinical and radiological data, morphology, immunohistochemistry, molecular features, and treatment to enhance the clinical and pathological understanding of PLNTY with FGFR3-TACC3 fusion for all professionals involved in medical decisions.

Real-world data on patients with ROS1-positive advanced non-small cell lung cancer (NSCLC) remain scarce. In this descriptive observational retrospective cohort study, we describe characteristics, treatments, and real-world progression-free survival (rwPFS) and overall survival (OS) among patients with ROS1-positive advanced NSCLC (de novo or recurrent) using secondary data pooled from clinical sites in Canada, France, Germany, Portugal, and Spain as part of the Oncology Evidence Network. Site-specific patient inclusion periods occurred between 2009 and 2023, with follow-up to 2024, allowing ≥1 year of potential follow-up at each site. In total, 108 patients were included, with most (n = 105; 97.2%) having a de novo diagnosis of advanced NSCLC. 103 patients (95.4%) received ≥1 line of systemic anticancer therapy (SACT), of which 65 (63.1%) received first-line targeted therapy, mostly crizotinib monotherapy (n = 45) or crizotinib-based regimens (n = 10), with a median (95% CI) rwPFS and OS of 14.0 (8.3-19.8) and 47.9 (27.3-not estimable) months, respectively. Thirty-eight of the 103 SACT-treated patients (36.9%) received first-line non-targeted therapy, mostly platinum-based chemotherapy (n = 26); median (95% CI) rwPFS and OS were 9.0 (7.5-11.0) and 29.3 (17.7-65.7) months, respectively. Results from this study indicated a tendency for longer survival using currently available ROS1-targeted versus non-targeted therapy for patients with ROS1-positive advanced NSCLC. Nevertheless, survival outcomes were limited, highlighting the importance of more effective emerging treatments for ROS1-positive disease.

KRAS-targeted therapy has opened new doors in the world of oncology, and many trials are underway for KRAS specific treatments for gastrointestinal (GI) malignancies. Outlining the current state of KRAS therapy and the remaining research gaps pertaining to these deadly cancers is crucial for the development of future therapeutics. In this review, we focus on the relationship between KRAS and GI malignancies. Current therapies are discussed with an in-depth exploration of the KRAS gene and how it connects to pancreatic, colorectal and other GI malignancies. Promising clinical trials and future therapies are highlighted while discussing the molecular biology behind them. Specifically, trials focusing on upcoming KRAS on and off inhibitors in development as well as variant focused inhibitors targeting the more common mutations G12D and G12V. We discuss exciting new pan/multi KRAS inhibitors that have been successful in pre-clinical trials. More unique therapeutic options include KRAS T cell therapies, vaccines, and combination strategies with immunotherapy. Furthermore, we address the difficulties with KRAS therapy, and the potential future directions needed to overcome them. An in-depth current literature review was done along with a review of the active clinical trials for KRAS-targeted therapeutics involving GI malignancies.

Juvenile nasopharyngeal angiofibroma (JNA), a rare vascular tumor in adolescent males, involves dysregulated angiogenesis and hormonal interplay. Key molecular drivers include HIF-1α, VEGF, bFGF, and β-catenin, promoting tumor growth via pathways like Wnt/β-catenin and Ras signaling. Androgens and estrogen modulate progression, though mechanisms remain debated. Targeted therapies reduce tumor proliferation and vascularity in preclinical studies, yet clinical translation is hindered by drug resistance and inconsistent biomarker expression. Hormonal and MMP-targeted approaches also show potential but require validation. This review consolidates JNA's molecular landscape, emphasizing the need for personalized strategies, biomarker refinement, and combination therapies to improve therapeutic outcomes for this challenging tumor.

Fear of cancer recurrence (FCR) is a significant but understudied concern among parents of childhood cancer survivors. This study quantitatively characterized parental FCR and explored potential demographic and clinical correlates among parents of children treated for cancer. Parents (N = 192) completed the Fear of Cancer Recurrence Inventory-Parent Short Form (FCRI-Parent) and provided demographic information. Clinical variables were obtained from medical chart review. Associations between FCR and demographic or clinical variables were analyzed using t-tests, ANOVAs, and Pearson's correlations. Parents reported a mean FCR score of 18.64 (SD = 8.73), with 42.2% of parents endorsing FCR above a score of 22. Parental FCR significantly varied by parent race, education, and spirituality. Higher FCR was also significantly negatively correlated with child age, time since diagnosis, and time since treatment completion. Parents of children with central nervous system tumors or hematological malignancies endorsed significantly higher FCR compared to parents of children with solid tumors. Findings build on previously identified psychosocial needs for parents of children treated for cancer by quantitatively describing parental FCR and exploring subgroups that may be at increased risk for FCR. Tailored interventions, including strategies that support spiritual coping, may help mitigate FCR among at-risk parents.

Uterine serous carcinoma (USC) represents a rare but aggressive subtype of endometrial cancer, accounting for a disproportionate number of disease-related deaths. Although molecular classification has improved risk stratification, prognostic heterogeneity highlights the need for new prognostic markers.

Tumor Mutational Burden (TMB) is a critical biomarker used to determine patient eligibility for immunotherapy with immune checkpoint inhibitors. However, its gold-standard assessment via whole exome sequencing is limited by high costs, technical complexity, and lengthy processing times. To address these challenges, we investigated whether Ultra-High-Frequency (UHF) electromagnetic wave sensing could serve as an alternative method for evaluating TMB. We analyzed the dielectrophoresis crossover frequency spectrum and corresponding electromagnetic signature (EMS) of cancer cells using a lab-on-a-chip biosensor that integrates microfluidics with dielectrophoresis-based electro-manipulation. Across seven solid tumor cell lines exhibiting diverse TMB levels, EMS exhibited an upward shift correlated with higher TMB, suggesting a relationship between mutational load and electromagnetic behavior. To further explore this connection, we artificially increased the somatic variant burden by exposing cells to the mutagen N-ethyl-N-nitrosourea (ENU). EMS measurements reliably detected the induced increase in variant load in ENU-treated cells. Overall, these findings demonstrate that EMS can detect both intrinsic TMB differences and experimentally induced increases in mutational burden, enabling refined categorization of cancer cells. Although further validation is required, this work lays the foundation for developing complementary, rapid, and accessible tools to support cancer cell stratification and guide immunotherapy decision-making.

Radiotherapy remains an irreplaceable treatment modality for breast cancer (BC). Calmodulin‑binding Transcription Activator 1 (CAMTA1) has been implicated in tumor progression; however, its role in BC is unclear. The present study aimed to elucidate the mechanistic function of CAMTA1 in BC. RNA sequencing was performed on RAW264.7 macrophages co‑cultured with 4T1 cells and subjected to X‑ray irradiation. In vitro, THP‑1 cells were co‑cultured with MDA‑MB‑231 cells under hypoxic conditions. Exosome morphology was observed under transmission electron microscopy and PKH67 staining was used to trace exosome uptake. Flow cytometry was used to detect CD163 expression while ELISA measured the levels of IL‑10 and IL‑12. Reverse transcription‑quantitative (RT‑q) PCR and immunoblotting analysis were used to detect the expressions of neuregulin 1 (NRG1), CAMTA1 and hypoxia‑inducible factor‑1α. Cell apoptosis, cell cycle distribution, cell viability and proliferation were evaluated using flow cytometry, MTT assay and colony formation assay. In vivo, transfected MDA‑MB‑231 cells were injected into BALB/c nude mice combined with radiotherapy and exosome injection. Histopathological changes in tumor tissues were examined using H&E staining. Immunohistochemistry analysis was performed to assess the expressions of NRG1, Caspase‑3 and CD163. RNA sequencing, RT‑qPCR and immunoblotting analysis revealed that NRG1 expression was markedly increased in RAW264.7 macrophages co‑cultured with 4T1 cells. NRG1 was found to be involved in M2 polarization induced by hypoxia‑treated MDA‑MB‑231 cells, which in turn promoted radio‑resistance. CAMTA1 expression was highly expressed in exosomes derived from hypoxic MDA‑MB‑231 cells and exosomal CAMTA1 promoted the M2 polarization of THP‑1 macrophages. In vivo, CAMTA1 overexpression greatly enhanced tumor growth, increased NRG1 expression, inhibited cell apoptosis and promoted M2 polarization of macrophages in tumor tissue. MDA‑MB‑231 cells were found to deliver CAMTA1 to macrophages via exosomes, leading to upregulation of NRG1 and induction of M2 polarization, thereby enhancing BC cells resistance to radiotherapy. These findings provided novel insights into the mechanisms underlying radio‑resistance in BC and identify exosomal CAMTA1 as a potential therapeutic target.

Ovarian cancer (OV) remains the most lethal gynecological malignancy, owing to late‑stage diagnosis, high metastatic potential and limited therapeutic efficacy. Although the transcription factor zinc finger and BTB domain‑containing 7A (ZBTB7A) has been implicated in several types of cancer, its role in OV has not yet been systematically characterized. The present study comprehensively investigated the expression pattern, prognostic relevance, functional role and downstream mechanisms of ZBTB7A in OV progression. Multi‑cohort transcriptomic analyses across independent public datasets revealed consistent upregulation of ZBTB7A in OV tissues, and high expression predicted a significantly poor prognosis. Single‑cell RNA sequencing demonstrated that ZBTB7A‑high tumor cells were enriched in proliferative, migratory and epithelial‑mesenchymal transition‑related programs, accompanied by activation of oncogenic pathways such as Wnt/β‑catenin and Hippo‑YAP. Functional assays using overexpression and RNA interference demonstrated that ZBTB7A enhanced malignant phenotypes, including increased cell proliferation, DNA synthesis, clonogenic survival and migration. Further analyses identified cytokine receptor‑like factor 1 (CRLF1) as a key downstream effector of ZBTB7A. ZBTB7A overexpression elevated CRLF1 transcription, whereas CRLF1 knockdown abrogated ZBTB7A‑induced proliferation and migration, defining a functional ZBTB7A/CRLF1 oncogenic axis. Collectively, these findings establish ZBTB7A as an important transcriptional driver of OV aggressiveness and highlight the ZBTB7A/CRLF1 regulatory pathway as a potential prognostic biomarker and therapeutic target.

Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is a multifunctional protein belonging to the heterogeneous nuclear ribonucleoprotein family. The K‑homology domain is the most evolutionarily conserved feature of hnRNPK and is responsible for RNA‑binding. hnRNPK interacts with both chromatin and RNA in numerous species. Initially characterized as an RNA‑binding protein, hnRNPK functions as a structural protein, integrating a number of signaling pathways and participating in gene expression regulation, RNA processing, cell cycle control and apoptosis. hnRNPK exhibits aberrant expression in numerous tumors, functioning paradoxically as either an oncogene or tumor suppressor depending on cellular context, expression levels and post‑translational modifications. Recent advancements have outlined the involvement of hnRNPK in tumor cell migration, angiogenesis and chemoresistance through interactions with long non‑coding RNAs and the regulation of key signaling pathways. The present review summarizes current knowledge regarding the structure, function and clinical importance of the hnRNPK in cancer, highlighting its potential as both a biomarker and therapeutic target.

Metaplastic breast carcinoma (MBC) is a heterogenous group of invasive breast cancer with distinct morphological patterns and negativity for hormone receptors and HER2. The pathogenesis of MBC is unknown but tumour cells exhibit epithelial-mesenchymal transition and breast cancer stem cell-like characteristics. Genomic characterisation of these tumours can lead to identification of targetable mutations which may help in improving the overall treatment outcome. Sixty-seven retrospective cases of MBC were sub-classified morphologically. Cytoplasmic expression of ALDH1 was evaluated using IHC to estimate the stemness. Alteration in PI3K/AKT/PTEN/MAPK pathway was studied using next generation sequencing (n = 47). Histological subtypes were squamous cell carcinoma (n = 25), Metaplastic carcinoma with heterologous mesenchymal differentiation (n = 19), spindle cell carcinoma (n = 19), Fibromatosis like metaplastic carcinoma (n = 3), and Mixed metaplastic carcinoma (n = 1). ALDH1 was positive in 31.3% cases. PI3K was the most frequently altered gene followed by PTEN, TP53 and MAPK1 gene. PI3K alterations were more frequent in Spindle cell carcinoma and squamous carcinoma This study identified high frequency of stem cell marker and targetable genetic alterations in the PI3K signalling pathway. Thus, Inhibitors of the PI3K signalling pathway are ideal candidates for targeted therapy for MBC irrespective of histological subtype.

Among pituitary adenomas, prolactin‑secreting pituitary neuroendocrine tumours (PRL‑PitNETs) are unique in that pharmacotherapy, specifically cabergoline (CAB), can be used as a first‑line treatment, and it is the recommended therapeutic option. However, the mechanisms underlying CAB resistance remain incompletely understood. In the present study, gene microarray analysis and clinical tissue specimens were used to identify circular RNAs (circRNAs) associated with CAB resistance. circOMA1 expression was quantified in PRL‑PitNET tissues and patient plasma using reverse transcription‑quantitative PCR, and its diagnostic potential was evaluated in 219 patients with pituitary adenoma. Gain‑ and loss‑of‑function assays, combined with molecular biology techniques, were used to investigate the biological function of circOMA1 and the underlying molecular mechanism. circOMA1 was identified as a critical circular RNA influencing CAB resistance and prognosis in PRL‑PitNET. Mechanistically, circOMA1 acted as a miR‑145‑5p sponge, leading to upregulation of the E3 ubiquitin ligase Kelch‑repeat and BTB domain‑containing protein 7. This promoted ubiquitination of the CAB‑specific, high‑affinity G‑protein‑coupled receptor dopamine D2 receptor. Consequently, downstream autophagy was attenuated, and AKT pathway inhibition was impaired, which underlied the resistance. Furthermore, in vitro and in vivo studies demonstrated that circOMA1 was transported via exosomes, facilitating the transmission of CAB resistance among PRL‑PitNET cells. Plasma exosomal circOMA1 levels were significantly elevated in PRL‑PitNET patients preoperatively. These findings established circOMA1 as a key mediator of CAB resistance and a potential prognostic indicator in patients with a PRL‑PitNET.

Bladder cancer is a challenging disease with high recurrence rates and limited treatment options. Studies have highlighted the role of ferroptosis, an iron‑dependent cell death mechanism, in cancer progression and treatment. In the present study, the regulatory mechanisms of polyphyllin II (PPII) on ferroptosis in bladder cancer cells were investigated. Cell viability and colony formation assays demonstrated that PPII effectively inhibited the proliferation of bladder cancer cells. RNA sequencing analysis revealed differentially expressed genes upon PPII treatment, with Cluster 6 exhibiting dose‑dependent expression changes. Gene Ontology and pathway enrichment analyses revealed enrichment of ferroptosis‑related pathways. PPII treatment markedly increased reactive oxygen species (ROS) levels and promoted Fe²+ accumulation in bladder cancer cells. Additionally, PPII downregulated the expression of glutathione peroxidase 4 (GPX4), a key regulator of ferroptosis. These findings indicate that PPII promotes ferroptosis in bladder cancer cells through the modulation of ROS levels and GPX4 activity. Further investigations into the molecular mechanisms and potential combination therapies are warranted.

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that, regarding the cell migration assay data shown in Fig. 4A on p. 432, the 'EC109' and 'Vector' data panels were found to contain an overlapping section, such that data which were intended to show the results of differently performed experiments were apparently derived from the same original source. The authors have been contacted by the Editorial Office to offer an explanation for the apparent anomaly in the presentation of the data in their paper, and we are awaiting their response. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of this potential problem while the Editorial Office continues to investigate this matter further. [International Journal of Molecular Medicine 27: 429-434, 2011; DOI: 10.3892/ijmm.2011.603].

Drug therapy serves a key role in the treatment of cervical cancer, which is one of the most common types of solid tumor in female patients. Therefore, it is important to seek more effective and less toxic therapies. Protein arginine methyltransferase 5 (PRMT5) is a key oncogenic target in cervical cancer, providing a rational basis for the development of targeted therapeutic agents. MS4322 is a highly selective proteolysis targeting chimera degrader specifically targeting PRMT5. Therefore, the present study aimed to investigate the therapeutic potential of MS4322 against cervical cancer and the underlying molecular mechanisms. The effects of MS4322 on human cervical HeLa cells were investigated by Cell Counting Kit‑8, clone formation, wound healing and Transwell assay, flow cytometry, immunofluorescence staining, immunohistochemistry and small interfering RNA assay. PRMT5 expression was upregulated in cervical cancer tissue, and functional analyses confirmed that PRMT5 promoted the proliferation of cervical cancer cells. MS4322 significantly decreased PRMT5 mRNA expression, as well as the proliferation, migration, invasion and clone formation ability of HeLa cells, leading to cell cycle arrest in G0/G1 phase and inducing apoptosis. Mechanistically, MS4322 downregulated the expression of PRMT5, β‑catenin, Wnt‑3a, and c‑myc, while upregulating GSK‑3β, thereby inactivating the Wnt/β‑catenin pathway. These findings indicated that MS4322 exerted anti‑tumor effects via regulating the PRMT5/Wnt/β‑catenin pathway and may serve as a promising candidate agent for cervical cancer treatment.

MicroRNAs (miRNAs or miRs) are a class of small non‑coding RNAs that are critical regulators of gene expression. By targeting messenger RNAs, they play essential roles in various biological processes, including development, differentiation, immunity, metabolism and apoptosis. miRNA dysregulation is often associated with tumorigenesis and cancer progression. miR‑124, a miRNA predominantly and specifically expressed in the central nervous system, is commonly downregulated in various cancers. It inhibits multiple malignant traits, including tumor growth, metastasis, stemness and chemoresistance. Furthermore, miR‑124 influences the tumor microenvironment and modulates antitumor immune responses. These diverse functions highlight their significant potential for clinical application. Its expression is modulated by various upstream factors, including transcription factors, signaling pathways, epigenetic modifications, and other non‑coding RNAs. However, the precise mechanisms governing this upstream regulation require further investigation. Despite this, the translational application of miR‑124 for early cancer diagnosis and therapy faces several significant challenges, including improving its stability and bioavailability and developing effective in vivo delivery systems. The present study provides a comprehensive overview of the multifaceted roles of miR‑124 in cancer, elucidating its underlying molecular mechanisms and exploring its clinical potential. By synthesizing the current literature, it was aimed to consolidate the current understanding of miR‑124 and identify promising avenues for future research.

The molecular classification of endometrial carcinomas (ECs) is now integrated into clinical practice. However, identification of polymerase-ε (POLE) variants remains reliant on DNA sequencing, which limits broader implementation. Given the strong prognostic value of pathogenic POLE mutations and the established efficacy of immunohistochemistry (IHC) for detecting mismatch repair (MMR) deficiency and p53 abnormalities, there is a clear need for IHC-based screening strategies to identify patients likely to carry POLE variants and prioritize them for confirmatory sequencing. In this study, we analyzed 24 cases with POLE pathogenic mutations (POLEmut ECs), 3 with benign POLE variants, and 32 matched cases with no specific molecular profile (NSMP) from a cohort of 378 ECs. IHC evaluation of the ataxia telangiectasia mutated (ATM) protein revealed that POLE-mutated ECs (with pathogenic or benign POLE variants) exhibited significantly higher frequencies of non-diffuse positive staining patterns, including null, heterogeneous positive, and subclonal loss, compared with NSMP cases. Targeted next-generation sequencing of all exons across 474 cancer-related genes in the 27 POLE-mutated ECs and 20 NSMP cases with ATM non-diffuse positive staining patterns confirmed that POLE-mutated ECs typically had high tumor mutational burden and were enriched for ATM truncating variants. ATM molecular alterations, including various variant subtypes and multisite mutations, also closely correlated with these staining patterns. Based on these findings, we refined the ATM IHC interpretation framework to integrate staining patterns with sequencing data for improved molecular correlation. Specifically, the null and subclonal loss patterns showed high specificity (96.9%), positive predictive value (94.1%), and accuracy (79.7%) for identifying POLE variants. Notably, the null pattern appeared exclusively in ECs with pathogenic POLE mutations. These results suggest that ATM IHC staining is an effective screening tool for identifying patients who may benefit from confirmatory POLE sequencing among those lacking MMR deficiency or p53 abnormalities.

Cerebral cavernous malformations (CCMs) are vascular lesions in the central nervous system that can cause strokes and seizures. Aggressive CCM growth follows an endothelial cell two-hit mechanism in which enhanced MEKK3-KLF2/4 signaling stimulates PI3K signaling, but how these pathways are linked has been undefined. Here, we use human CCM specimens, two mouse models of CCM disease, and primary human endothelial cells to examine the roles of the major endothelial growth factor receptors, VEGFR2 and TIE2. We find no evidence of augmented VEGFR2 signaling in CCM lesions, and neither genetic nor pharmacologic blockade of VEGFR2 reduced CCM formation in mouse models. Instead, we observe markedly increased phospho-TIE2 levels in human and mouse CCM lesions, MEKK3-KLF2/4-driven induction of TIE2 receptor expression, and almost complete rescue of CCM formation following genetic or pharmacologic TIE2 blockade in mouse models. Our studies identify TIE2 as the molecular link between the MEKK3-KLF2/4 and PI3K signaling pathways during CCM formation and suggest that targeting TIE2 may be an effective means to treat human CCM disease.

TFE3-rearranged perivascular epithelioid cell tumor (PEComa)-like neoplasm is a recently described entity. Here, we report a rare TFE3-rearranged PEComa-like neoplasm in a 37-year-old female patient exhibiting unusual morphologic and immunohistochemical features and a novel ZBED6::TFE3 fusion.