Search

Embryonic and early postnatal promotor-driven deletion of the phosphatase and tensin homolog (PTEN) gene results in neuronal hypertrophy, hyperexcitable circuitry and development of spontaneous seizures in adulthood. We previously documented that focal, vector-mediated PTEN deletion in mature granule cells of adult dentate gyrus triggers dramatic growth of cell bodies, dendrites, and axons, similar to that seen with early postnatal PTEN deletion. Here, we assess the functional consequences of focal, adult PTEN deletion, focusing on its pro-epileptogenic potential. PTEN deletion was accomplished by injecting AAV-Cre either bilaterally or unilaterally into the dentate gyrus of double transgenic PTEN-floxed, ROSA-reporter mice. Hippocampal recording electrodes were implanted for continuous digital EEG with concurrent video recordings in the home cage. Electrographic seizures and epileptiform spikes were assessed manually by two investigators, and corelated with concurrent videos. Spontaneous electrographic and behavioral seizures appeared after focal PTEN deletion in adult dentate granule cells, commencing around 2 months post-AAV-Cre injection. Seizures occurred in the majority of mice with unilateral or bilateral PTEN deletion and led to death in several cases. PTEN-deletion provoked epilepsy was not associated with apparent hippocampal neuron death; supra-granular mossy fiber sprouting was observed in a few mice. In summary, focal, unilateral deletion of PTEN in the adult dentate gyrus suffices to provoke time-dependent emergence of a hyperexcitable circuit generating hippocampus-origin, generalizing spontaneous seizures, providing a novel model for studies of adult-onset epileptogenesis.

PTEN Hamartoma Tumor Syndrome (PHTS) is an autosomal dominant disorder characterized by high penetrance and significant phenotypic variability. In most patients, targeted high-throughput sequencing (HTS) approaches enable the detection of loss-of-function pathogenic variants in PTEN, a tumor suppressor gene acting as a negative regulator of the PI3K-AKT pathway. We describe a patient exhibiting a clinical phenotype strongly indicative of PHTS, yet lacking a molecular diagnosis through PTEN-targeted HTS. After several years of diagnostic uncertainty, trio whole genome sequencing (WGS) ultimately identified a de novo germline deep intronic 98 bp deletion in PTEN intron 5 (c.492 + 1671_492 + 1768del). Targeted RNA sequencing revealed the inclusion of a pseudoexon, resulting in a frameshift and predicted protein truncation at codon 171 (p.Val166Asnfs*6). These data underline the importance of WGS approaches in detecting deep intronic structural variants, that may be overlooked by conventional methods. [ABSTRACT FROM AUTHOR]

Epigenetic alterations, especially promotor methylation, have a significant impact on gene expression, molecular subtyping, prognosis, and outcome of breast cancer (BC). The methylation profile was assessed for 22 genes of the BC tissue using the EpiTect Methyl II PCR System in 40 triple-negative BC (TNBC) patients compared to 50 non-TNBC group. The data were corelated with the disease-free (DFS) and overall survival (OS) of the patients. Genes that were differentially hypermethylated in TNBC patients compared to those with non-TNBC included CCND2, CDKN2A, ESR1, CDH1, BRCA1, GSTP, RASSF1, SLIT2, MGMT, PTEN, TP73, and PRDM2. These panel achieved 95% sensitivity, 98% specificity, 97.44% positive predictive value (PPV), 94.23% negative predictive value (NPV), and AUC of 0.993. Hypermethylation of BRCA1, CDH1, CDKN2A, ESR1, GSTP, HIC1, MGMT, PRDM2, PTEN, PYCARDM, RASSF1M, THBS1, and TP73 associated significantly with worse OS and DFS in TNBC cohort. Meanwhile, CCNA1 and CDH1 hypermethylation demonstrated significant associations with poor DFS but did not show significant relationships with OS in TNBC patients. PTGS2 and TNFRSF10C methylation were associated with better DFS and OS rates in TNBC patients. On multivariate Cox regression, CCND2 and PTEN hypermethylation were independent predictors of DFS in the overall BC patients. The hypermethylation of BRCA1 and GSTP were independent predictors of DFS, while PTEN hypermethylation was an independent predictor of OS in the TNBC cohort. The identification of hypermethylated genes, such as BRCA1, CCND2, CDH1, ESR1, GSTP, RASSF1, SLIT2, MGMT, and PTEN may serve as potential biomarkers or therapeutic targets for TNBC. [ABSTRACT FROM AUTHOR]

Purpose: Colorectal cancer (CRC) is among the most common malignant tumors worldwide, posing a significant threat to human health. Most patients with CRC are refractory to existing treatment regimens, such as immune checkpoint blockades (ICBs), yielding unsatisfactory outcomes. This study aimed to explore the effect and mechanism of a natural product, indole-3-carbinol (I3C), in CRC pathogenesis and immunotherapy. Methods: A series of in vitro experiments, such as the cell counting kit-8 and wound healing assays, were used to assess the proliferative, colony-formating and migratory capacity of human CRC cells after I3C treatment. In vivo experiment, xenograft growth assay was conducted to verify the effect of I3C on CRC. Hematoxylin–eosin (HE) staining was utilized to evaluated the toxic effect of I3C. Immunohistochemical staining was used to detect CD8+ T cell infiltration. Subcutaneous CRC models constructed in immunocompetent mice were used to test the effects of I3C treatment in combination with PD1ab therapy. The Human Protein Atlas (HPA) database, cell transfection, and quantitative real-time polymerase chain reaction (RT-qPCR) experiments were used to explore the mechanism of I3C in CRC. Results: I3C significantly inhibited CRC cell proliferation, colony formation, and migration capacity in vitro and in vivo. The result of HE staining indicated that I3C exert no significant toxic effect on heart, liver and kidney. HPA data analysis and RT-qPCR results demonstrated that PTEN expression was lower in CRC tissues than in normal tissues or cells. Besides, I3C exerted antitumor activity and promoted CD8+ T cell infiltration by upregulating PTEN expression. Consequently, I3C, in conjunction with PD1ab therapy, synergistically enhanced the antitumor effect on CRC in immunocompetent mice. Conclusions: These findings suggested that by upregulating PTEN expression, the natural product I3C strongly prevented tumor progression and exerted no systematic toxicity in the major organs such as heart, kidney and liver. Furthermore, I3C significantly enhanced PD1ab therapeutic effect in CRC, highlighting its role as a candidate preventive or therapeutic compound for CRC therapy, especially in combination with PD1ab therapy. Further clinical trial should be conducted in the future. [ABSTRACT FROM AUTHOR]

Background: Renal cell carcinoma (RCC) is a frequent and aggressive type of kidney cancer with limited therapeutic options. Although phosphatase and tensin homolog (PTEN) have been recognized as a potential tumor suppressor in all kinds of cancers, its function in RCC remains to be thoroughly elucidated. Objective: This article was recruited to examine the PTEN's role in managing the PI3K/AKT pathway and its impact on the RCC cell proliferation and migration. Methods: This study collected renal cancer and adjacent non-cancerous tissue samples from our hospital. HK-2 and 786-O cells were used, with 786-O cells divided into control, vector, and oe-PTEN groups. PTEN and related protein levels were detected using RT-qPCR and Western blot. Statistical analyses were performed using the Mann-Whitney U test and Kruskal-Wallis H test. Cell viability and migration were assessed using the CCK-8 assay and wound healing assay. All analyses were conducted with SPSS 22.0 software, with statistical significance defined as p < 0.05. Results: RT-qPCR results showed that PTEN expression was significantly increased in RCC tumor tissues compared to normal tissues (p < 0.01). However, PTEN mRNA levels were significantly reduced in 786-O cells compared to HK-2 cells (p < 0.01). In 786-O cells with low PTEN expression, further induction of PTEN overexpression significantly inhibited PI3K/AKT signaling activity (p < 0.01), accompanied by decreased cell viability and migration ability. These results indicate that the expression pattern of PTEN in RCC is complex, but its overexpression can exert tumor-suppressive effects by inhibiting the PI3K/AKT signaling pathway. Conclusion: Our findings demonstrate that PTEN overexpression in RCC cells leads to decreased PI3K/AKT signaling, decreasing cell viability and migration. This study highlights the critical role of PTEN in RCC progression and suggests potential therapeutic targets for intervention. [ABSTRACT FROM AUTHOR]

Reproductive cancers, including prostate and ovarian cancer, are highly prevalent worldwide and pose significant health challenges. The molecular underpinnings of these cancers are complex and involve dysregulation of various cellular pathways. Understanding these pathways is crucial for developing effective therapeutic strategies. This review aims to provide an overview of the molecular pathways implicated in prostate and ovarian cancers, highlighting key genetic alterations, signaling cascades, and epigenetic modifications. A comprehensive literature search was conducted using databases such as PubMed, Web of Science, and Google Scholar. Articles focusing on molecular pathways in prostate and ovarian cancer were reviewed and analyzed. In prostate cancer, recurrent mutations in genes like AR, TP53, and PTEN drive tumor growth and progression. Androgen signaling plays a significant role, with alterations in the AR pathway contributing to resistance to antiandrogen therapies. In ovarian cancer, high-grade serous carcinomas are characterized by mutations in TP53, BRCA1/2, and homologous recombination repair genes. PI3K and MAPK pathways are frequently activated, promoting cell proliferation and survival. Epigenetic alterations, including DNA methylation and histone modifications, are also prevalent in both cancer types. The molecular pathways involved in prostate and ovarian cancer are diverse and complex. Targeting these pathways with precision medicine approaches holds promise for improving patient outcomes. Further research is needed to elucidate the mechanisms of resistance and identify novel therapeutic vulnerabilities. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Is there an association between the somatic loss of PTEN (phosphatase and tensin homolog) and ARID1A (AT-rich interaction domain 1A) and endometriosis disease severity and worse clinical outcomes? SUMMARY ANSWER Somatic PTEN loss in endometriosis epithelium was associated with greater disease burden and subsequent surgical complexity. WHAT IS KNOWN ALREADY Somatic cancer-driver mutations including those involving the PTEN and ARID1A genes exist in endometriosis without cancer; however, their clinical impact remains unclear. STUDY DESIGN, SIZE, DURATION This prospective longitudinal study involved endometriosis tissue and clinical data from 126 participants who underwent surgery at a tertiary center for endometriosis (2013–2017), with a follow-up period of 5–9 years. PARTICIPANTS/MATERIALS, SETTING, METHODS PTEN and ARID1A loss was assessed using established immunohistochemistry (IHC) methods as proxies for somatic loss by two independent raters. PTEN and ARID1A status for each participant was defined as loss (loss in at least one sample for a participant) or retained (no loss in all samples for a participant). Primary analyses examined associations between PTEN and ARID1A loss and disease burden based on anatomic subtype (superficial peritoneal endometriosis (SUP), deep endometriosis (DE), ovarian endometrioma (OMA)) and rASRM stage (I–IV). Secondary analyses explored associations of PTEN and ARID1A loss with demographics, surgical difficulty, and pain scores (baseline and follow-up). Additionally, using previously published data on KRAS codon 12 mutations for this cohort, we investigated associations between variables in the primary and secondary analyses and acquiring two or more somatic events (PTEN loss, ARID1A loss, or KRAS mutation) in this cohort. The risk of reoperation over the 5–9 years was also examined. MAIN RESULTS AND THE ROLE OF CHANCE PTEN loss (68.3%; 86 participants) exceeded ARID1A loss (24.6%; 31 participants). Inter-rater reliability was substantial for PTEN (k  = 0.69; 95% CI: 0.62–0.77) and ARID1A (k  = 0.64; 95% CI: 0.51–0.77). PTEN loss was significantly associated with more severe anatomic subtypes (P  < 0.001; participants with SUP only = 46.4%; participants with DE only or OMA only = 72.7%; participants with mixed subtypes = 85.1%), and higher stages (P  = 0.024; Stage I = 47.8%; Stage II = 73.7%; Stage III = 80.8%; Stage IV = 81.0%). Results were similar for ARID1A loss, albeit with smaller sample size limiting power. PTEN loss was further associated with non-White ethnicities (P  = 0.017) and greater surgical difficulty (more frequent need for ureterolysis) (P  = 0.02). There were no differences in pain scores (baseline or follow-up) based on PTEN or ARID1A status. Reoperation was uncommon (13.5% of the cohort), and patterns in reoperation rates based on the presence of somatic alterations did not reach statistical significance. LIMITATIONS, REASONS FOR CAUTION Sequencing was not performed to determine the type of PTEN and ARID1A somatic mutations resulting in loss of expression. WIDER IMPLICATIONS OF THE FINDINGS These results demonstrate a link between PTEN somatic loss and greater endometriosis disease burden. These findings underscore the potential relevance of PTEN loss and other somatic driver mutations in a future molecular classification of endometriosis. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by Canadian Institutes of Health Research (CIHR) project grant (MOP-142273 and PJT-156084). P.J.Y. was supported by a Health Professional Investigator award from Michael Smith Health Research BC, Canada, and a Canada Research Chair (Tier 2) in Endometriosis and Pelvic Pain. M.S.A. was supported by a Michael Smith Health Research BC Scholar award, and CIHR project grants (369990, 462997, and 456767). The sponsors did not play any role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. C.A. declares receiving payment from Pfizer for a symposium; being on advisory boards for AbbVie and Pfizer; being President and past President of the Canadian Society for the Advancement of Gynecologic Excellence (CanSAGE), co-lead of EndoAct Canada, and a board member of IPPS. M.A.B. has received consulting fees from AbbVie and Pfizer and grants from Ferring outside the scope of this work. D.G.H. is the founder of Canxeia Health but has no current affiliation. M.K. has received consulting fees from Helix Biopharma outside the scope of this work. M.S.A. received reimbursement of travel and registration fees to attend and present at the 2023 and 2024 annual meetings for the Society for Reproductive Investigation (SRI). P.J.Y. declares receiving: payment for a lecture from the International Society for the Study of Women's Sexual Health (ISSWSH); honoraria from the CIHR; support to attend meetings from CanSAGE, ISSWSH, the International Pelvic Pain Society, the World Endometriosis Society (WES), the Society for the Study of Reproduction, and the Vulvodynia Summit; and discounted devices from Ohnut Wearable for a clinical trial. P.J.Y. is a data safety monitoring board member of a clinical trial funded by CIHR; and a strategic advisory board member for the Women's Health Research Institute. P.J.Y. served as a board of directors member for CanSAGE and ISSWSH; was a junior board of directors member for WES; is a current board of directors member for WES; and was a committee chair for the Society of Obstetricians and Gynaecologists of Canada. A subset of these results was presented by the first author at the 71st Society for Reproductive Investigation Annual Scientific Meeting on 15 March 2024. Other authors have nothing to declare. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Sleep deprivation (SD) impairs learning and memory. Investigating the role of epigenetic modifications, such as 5-methylcytosine (m5C), in SD is crucial. This study established an SD mouse model and assessed the mRNA levels of m5C-related genes in brain tissue to identify potential candidates. Results indicated a significant elevation of NSUN2 in the SD group. Behavioral assessments using the Morris water maze test revealed cognitive impairments. Notably, inhibiting NSUN2 markedly alleviated these cognitive deficits and reduced autophagy in SD mice. Mechanistically, NSUN2 inhibition led to a pronounced decrease in PTEN levels, and the m5C modification of PTEN, which was increased by SD, was significantly reduced following NSUN2 knockdown. It was found that NSUN2 stabilizes PTEN mRNA through methylation. In the SD group, PTEN protein levels were elevated, and this increase was counteracted by NSUN2 inhibition. Collectively, the upregulation of PTEN may diminish the beneficial effects of NSUN2 inhibition on cognitive function and autophagy in SD mice. This study suggests that targeting NSUN2 and PTEN could be a novel therapeutic approach to ameliorate cognitive impairments and autophagy associated with SD, offering a promising strategy for the clinical management of SD-related cognitive deficits. [ABSTRACT FROM AUTHOR]

Aggressive variant prostate cancer (AVPC) is characterized by a molecular signature involving combined defects in TP53, RB1, and/or PTEN (AVPC-TSGs), identifiable through immunohistochemistry or genomic analysis. The reported prevalence of AVPC-TSG alterations varies widely, reflecting differences in assay sensitivity, treatment pressure, and disease stage evolution. Although robust clinical evidence is still emerging, the study of AVPC-TSG alterations in prostate cancer (PCa) is promising. Alterations in TP53, RB1, and PTEN, as well as the combined loss of AVPC-TSGs, may have significant implications for prognosis and treatment. These biomarkers might help predict responses to various therapies, including hormonal treatments, cytotoxic agents, radiotherapy, and targeted therapies. Understanding the impact of these molecular alterations in patients with PCa is crucial for personalized management. In this review, we provide a comprehensive overview of the emerging prognostic and predictive roles of AVPC-TSG alterations across PCa stages. Moreover, we discuss the implications of different methods used for detecting AVPC-TSG alterations and summarize factors influencing their prevalence. As our comprehension of the genomic landscape of PCa disease deepens, incorporating genomic profiling into clinical decision making will become increasingly important for improving patient outcomes. [ABSTRACT FROM AUTHOR]

Chronic spinal cord injury (SCI) lesions retain increased densities of microglia and macrophages. In acute SCI, macrophages induce growth cone collapse and facilitate axon retraction away from lesion boundaries. Little is known about the role of sustained inflammation in chronic SCI or whether chronic inflammation affects regeneration. We used the colony-stimulating factor-1 receptor inhibitor, PLX-5622, to deplete microglia and macrophages months after complete crush SCI in female mice. Transcriptional analyses revealed a significant inflammatory depletion within chronic SCI lesions after PLX-5622 treatment. Both transcriptional analyses and immunohistochemistry revealed that Iba1+ cells repopulate to predepleted densities after treatment removal. Neuronal-enriched transcripts were significantly elevated in mice after inflammatory repopulation, but no significant effects were observed with inflammatory depletion alone. Axon densities also significantly increased within the lesion after PLX-5622 treatment and after repopulation. To better examine the effect of chronic inflammation on axon regeneration, we tested PLX-5622 treatment in neuronal-specific phosphatase and tensin homolog protein (PTEN) knock-out (PTEN-KO) mice. PTEN-KO was delivered using spinal injections of retrogradely transported adeno-associated viruses (AAVrg’s). PTEN-KO did not further increase axon densities within the lesion beyond the effects induced by PLX-5622. Axons that grew within the lesion were histologically identified as 5-HT+ and CGRP+, both of which are not robustly transduced by AAVrg’s. Our work identified that increased macrophage/microglial densities in the chronic SCI environment may be actively retained by homeostatic mechanisms likely affiliated with a sustained elevated expression of CSF1 and other chemokines. Finally, we identify a novel role of sustained inflammation as a prospective barrier to axon regeneration in chronic SCI. [ABSTRACT FROM AUTHOR]

Alpha fetoprotein (AFP) is a glycoprotein of foetal origin belonging to the albumin protein family. Serum AFP is a long‐conceived early‐diagnostic biomarker for HCC with its elevated expression in different liver pathologies ranging from hepatitis viral infections to fibrosis, cirrhosis, and HCC. Beyond their utility as biomarkers, in support of its contribution to these clinical outcomes, the function of AFP as an immune suppressor and inducer of malignant transformation in HCC patients is well reported. Multiple reports show that AFP is secreted by hepatocytes, binds to its cognate receptor, AFP‐receptor (AFPR), and exerts its actions. However, there is only limited information available in this context. There is an urgent need to gather more insight into the AFP signalling pathway and consider it a classical intracellular signalling pathway, among others. AFP is a highly potent intracellular molecule that has the potential to bind to many interactors like PTEN, Caspase, RAR, and so on. It has been shown that cellular AFP and secreted AFP have different roles in HCC pathophysiology, and a comprehensive map of the AFP signalling pathway is warranted for further theranostic applications. [ABSTRACT FROM AUTHOR]

Phosphatase and tensin homologue (PTEN) is the main antagonist of the phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR signalling pathway and mutated in 10%–20% of individuals with autism spectrum disorder (ASD) exhibiting macrocephaly. Hyperactive mTOR signalling is responsible for some aspects during PTEN-ASD progression, e.g. neuronal hypertrophy and -excitability, but PI3K/mTOR-independent processes have additionally been described. There is emerging evidence that PTEN regulates gene transcription, spliceosome formation and pre-mRNA splicing independently of PI3K/mTOR. Altered splicing is a hallmark of brains from individuals with idiopathic and PTEN-ASD, however, molecular mechanisms are yet to be identified. We performed RNA-sequencing (RNA-Seq), followed by analysis of altered transcript splicing in Pten -deficient primary cortical mouse neurons, which we compared with published data from PTEN -deficient human neuronal stem cells. This analysis identified that transcripts were globally mis-spliced in a developmentally regulated fashion and cluster in synaptic and gene expression regulatory processes. Strikingly, splicing defects following Pten -deficiency represent a significant number of other known ASD-susceptibility genes. Furthermore, we show that exons with strong 3′ splice sites are more frequently mis-spliced under Pten -deficient conditions. Our study indicates that PTEN-ASD is a multifactorial condition involving the dysregulation of other known ASD-susceptibility genes. [ABSTRACT FROM AUTHOR]

Background: PTEN hamartoma tumor syndrome (PHTS) has evolved into an umbrella term for a range of syndromes, characterized by loss-of-function variants in the phosphatase and tensin homolog (PTEN) tumor suppressor gene on chromosome 10q23.31. This can result in a lifelong tumor predisposition in patients. Often, the syndrome is diagnosed in early childhood because of macrocephaly, dermatological findings, or development delay. Since the correlation between phenotype and genotype is weak, and the penetrance is age-dependent, this poses the question of the appropriate timing of potentially invasive and burdensome examinations for early cancer detection. Case: The present report describes an infant with cleft palate associated with PHTS, a rare occurrence, though the initial report of Cowden syndrome already pointed to oromaxillofacial abnormalities. The recent pediatric literature is reviewed to assess which clinical symptoms should raise suspicion of PHTS and may then lead to early genetic counseling. Conclusion: Since the amount of prospective data remains limited, and the estimation of tumor risk during infancy and adulthood is very difficult, we advocate for early and broad genetic testing in suspected cases, to gain more insights into this rare disease and allow for better counseling for patients and their families. [ABSTRACT FROM AUTHOR]