OBJECTIVE: To comprehensively investigate the potential association between prostate cancer (PCa) and the G84E mutation within the Homeobox Protein B13 (HOXB13) gene among individuals of Turkish descent, our study aims to undertake a prospective examination.
METHODS: We evaluated 300 patients (150 diagnosed with prostate cancer, 150 controls) who presented in our clinic. Data collected were prospectively examined. DNA isolation was performed using an isolation kit. The HOXB13-G84E mutation (rs138213197) was analyzed in the obtained samples. Data encoding and statistical analysis were performed.
RESULTS: The pathological allele for the G84E mutation was T. According to the findings, no mutations were detected in the control group, while the G84E mutation was detected in 17 patients in the patient group, all of whom had the TC genotype. The analysis showed that having the CC genotype reduced the risk of prostate cancer by 0.47 times (OR=0.47, CI=0.415-0.532). Our results did not support a trend toward family history or earlier-onset disease in comparisons between carriers and non-carriers of HOXB13 G84E mutation. Individuals with a positive family history exhibited a higher frequency of the G84E mutation.
CONCLUSIONS: We concluded that HOXB13 gene mutation is indeed linked to PCa in Turkish men. However, we did not find a relationship between the HOXB13 gene G84E mutation carrier status and either early-onset PCa or familial PCa in Turkish men.

Fetal growth restriction (FGR) is a clinically important human pregnancy disorder that is thought to originate early in pregnancy and while its aetiology is not well understood, the disorder is associated with placental insufficiency. Currently treatment for FGR is limited by increased surveillance using ultrasound monitoring and premature delivery, or corticosteroid medication in the third trimester to prolong pregnancy. There is a pressing need for novel strategies to detect and treat FGR at its early stage. Homeobox genes are well established as master regulators of early embryonic development and increasing evidence suggests they are also important in regulating early placental development. Most important is that specific homeobox genes are abnormally expressed in human FGR. This review focusses on identifying the molecular pathways controlled by homeobox genes in the normal and FGR-affected placenta. This information will begin to address the knowledge gap in the molecular aetiology of FGR and lay the foundation for identifying potential diagnostic and therapeutic targets.

Placental insufficiency is one of the major causes of fetal growth restriction (FGR), a significant pregnancy disorder in which the fetus fails to achieve its full growth potential in utero. As well as the acute consequences of being born too small, affected offspring are at increased risk of cardiovascular disease, diabetes and other chronic diseases in later life. The placenta and heart develop concurrently, therefore placental maldevelopment and function in FGR may have profound effect on the growth and differentiation of many organ systems, including the heart. Hence, understanding the key molecular players that are synergistically linked in the development of the placenta and heart is critical. This review highlights the key growth factors, angiogenic molecules and transcription factors that are common causes of defective placental and cardiovascular development.

UNASSIGNED: Homeobox genes play an important role in health and disease including oncogenesis. The present investigation aimed to study ERN1-dependent hypoxic regulation of the expression of genes encoding homeobox proteins MEIS (zinc finger E-box binding homeobox 2) and LIM homeobox 1 family, SPAG4 (sperm associated antigen 4) and NKX3-1 (NK3 homeobox 1) in U87MG glioblastoma cells in response to inhibition of ERN1 (endoplasmic reticulum to nucleus signaling 1) for evaluation of their possible significance in the control of glioblastoma growth.
UNASSIGNED: The expression level of homeobox genes was studied in control (transfected by vector) and ERN1 knockdown U87MG glioblastoma cells under hypoxia induced by dimethyloxalylglycine (0.5 mM for 4 h) by quantitative polymerase chain reaction and normalized to ACTB.
UNASSIGNED: It was found that hypoxia down-regulated the expression level of LHX2, LHX6, MEIS2, and NKX3-1 genes but up-regulated the expression level of MEIS1, LHX1, MEIS3, and SPAG4 genes in control glioblastoma cells. At the same time, ERN1 knockdown of glioblastoma cells significantly modified the sensitivity of all studied genes to a hypoxic condition. Thus, ERN1 knockdown of glioblastoma cells removed the effect of hypoxia on the expression of MEIS1 and LHX1 genes, but increased the sensitivity of MEIS2, LHX2, and LHX6 genes to hypoxia. However, the expression of MEIS3, NKX3-1, and SPAG4 genes had decreased sensitivity to hypoxia in ERN1 knockdown glioblastoma cells. Moreover, more pronounced changes under the conditions of ERN1 inhibition were detected for the pro-oncogenic gene SPAG4.
UNASSIGNED: The results of the present study demonstrate that hypoxia affected the expression of homeobox genes MEIS1, MEIS2, MEIS3, LHX1, LHX2, LHX6, SPAG4, and NKX3-1 in U87MG glioblastoma cells in gene-specific manner and that the sensitivity of all studied genes to hypoxia condition is mediated by ERN1, the major pathway of the endoplasmic reticulum stress signaling, and possibly contributed to the control of glioblastoma growth. A fundamentally new results of this work is the establishment of the fact regarding the dependence of hypoxic regulation of SPAG4 gene expression on ER stress, in particular ERN1, which is associated with suppression of cell proliferation and tumor growth.

Conserved noncoding elements (CNEs) are DNA sequences located outside of protein-coding genes that can remain under purifying selection for up to hundreds of millions of years. Studies in vertebrate genomes have revealed that most CNEs carry out regulatory functions. Notably, many of them are enhancers that control the expression of homeodomain transcription factors and other genes that play crucial roles in embryonic development. To further our knowledge of CNEs in other parts of the animal tree, we conducted a large-scale characterization of CNEs in more than 50 genomes from three of the main branches of the metazoan tree: Cnidaria, Mollusca, and Arthropoda. We identified hundreds of thousands of CNEs and reconstructed the temporal dynamics of their appearance in each lineage, as well as determining their spatial distribution across genomes. We show that CNEs evolve repeatedly around the same genes across the Metazoa, including around homeodomain genes and other transcription factors; they also evolve repeatedly around genes involved in neural development. We also show that transposons are a major source of CNEs, confirming previous observations from vertebrates and suggesting that they have played a major role in wiring developmental gene regulatory mechanisms since the dawn of animal evolution.

The Modern Synthesis, a pillar in biological thought, united Darwin\'s species origin concepts with Mendel\'s laws of character heredity, providing a comprehensive understanding of evolution within species. Highlighting phenotypic variation and natural selection, it elucidated the environment\'s role as a selective force, shaping populations over time. This framework integrated additional mechanisms, including genetic drift, random mutations, and gene flow, predicting their cumulative effects on microevolution and the emergence of new species. Beyond the Modern Synthesis, the Extended Evolutionary Synthesis expands perspectives by recognizing the role of developmental plasticity, non-genetic inheritance, and epigenetics. We suggest that these aspects coexist in the plant evolutionary process; in this context, we focus on the saltational model, emphasizing how saltation events, such as dichotomous saltation, chromosomal mutations, epigenetic phenomena, and polyploidy, contribute to rapid evolutionary changes. The saltational model proposes that certain evolutionary changes, such as the rise of new species, may result suddenly from single macromutations rather than from gradual changes in DNA sequences and allele frequencies within a species over time. These events, observed in domesticated and wild higher plants, provide well-defined mechanistic bases, revealing their profound impact on plant diversity and rapid evolutionary events. Notably, next-generation sequencing exposes the likely crucial role of allopolyploidy and autopolyploidy (saltational events) in generating new plant species, each characterized by distinct chromosomal complements. In conclusion, through this review, we offer a thorough exploration of the ongoing dissertation on the saltational model, elucidating its implications for our understanding of plant evolutionary processes and paving the way for continued research in this intriguing field.

Having experienced stress during sensitive periods of brain development strongly influences how individuals cope with later stress. Some are prone to develop anxiety or depression, while others appear resilient. The as-yet-unknown mechanisms underlying these differences may lie in how genes and environmental stress interact to shape the circuits that control emotions. Here, we investigated the role of the habenulo-interpeduncular system (HIPS), a critical node in reward circuits, in early stress-induced anxiety in mice. We found that habenular and IPN components characterized by the expression of Otx2 are synaptically connected and particularly sensitive to chronic stress (CS) during the peripubertal period. Stress-induced peripubertal activation of this HIPS subcircuit elicits both HIPS hypersensitivity to later stress and susceptibility to develop anxiety. We also show that HIPS silencing through conditional Otx2 knockout counteracts these effects of stress. Together, these results demonstrate that a genetic factor, Otx2, and stress interact during the peripubertal period to shape the stress sensitivity of the HIPS, which is shown to be a key modulator of susceptibility or resilience to develop anxiety.

Homeodomain (HD)-containing proteins are typically recognized as transcription factors. Engrailed 2 (EN2) is an HD-containing protein that is highly expressed in various types of cancers, however, the mechanism underlying the biological function of EN2 is not fully understood. Here, we report a transcription-independent function of EN2 in addition to its role as a transcription factor. EN2 expression leads to the activation of multiple signaling pathways mediated by phosphorylation cascades. A phosphoproteomic analysis revealed that the phosphorylation status of numerous protein sites was altered after EN2 is expressed. Notably, EN2 was shown to interact with a myriad of proteins implicated in phosphorylation signaling cascades, as determined by immunoprecipitation-mass spectrometry (IP-MS). We validated the interaction between EN2 and B55α, the regulatory subunit of the PP2A-B55α complex, and confirmed that the phosphatase activity of the complex was suppressed by EN2 binding. To target EN2-induced malignancy, two kinds of small molecules were utilized to inhibit the EN2-activated NF-κB and AKT signaling pathways. A clear synergistic effect was observed when the activation of the two pathways was simultaneously blocked. Collectively, the data show that EN2 functions in a transcription-independent manner in addition to its role as a transcription factor. This finding may have therapeutic implications in treating esophageal squamous cell carcinoma (ESCC).

UNASSIGNED: Nonsyndromic craniofacial clefts are relatively common congenital malformations which could create a significant negative effect on the health status and life quality of affected individuals within the pediatric population. Multiple cleft candidate genes and their coded proteins have been described with their possible involvement during cleft formation. Some of these proteins like Homeobox Protein BarH-like 1 (BARX1), Distal-Less Homeobox 4 (DLX4), Forkhead Box E1 (FOXE1), Homeobox Protein Hox-B3 (HOXB3), and Muscle Segment Homeobox 2 (MSX2) have been associated with the formation of craniofacial clefts. Understanding the pathogenetic mechanisms of nonsyndromic craniofacial cleft formation could provide a better knowledge in cleft management and could be a possible basis for development and improvement of cleft treatment options. This study investigates the presence of BARX1, DLX4, FOXE1, HOXB3, and MSX2 positive cells by using immunohistochemistry in different types of cleft-affected tissue while determining their possible connection with cleft pathogenesis process.
UNASSIGNED: Craniofacial cleft tissue material was obtained during cleft-correcting surgery from patients with nonsyndromic craniofacial cleft diagnosis. Tissue material was gathered from patients who had unilateral cleft lip (n=36), bilateral cleft lip (n=13), and cleft palate (n=26). Control group (n=7) tissue material was received from individuals without any craniofacial clefts. The number of factor positive cells in the control group and patient group tissue was evaluated by using the semiquantitative counting method. Data was evaluated with the use of nonparametric statistical methods.
UNASSIGNED: Statistically significant differences were identified between the number of BARX1, FOXE1, HOXB3, and MSX2-containing cells in controls and cleft patient groups but no statistically significant difference was found for DLX4. Statistically significant correlations between the evaluated factors were also notified in cleft patient groups.
UNASSIGNED: HOXB3 could be more associated with morphopathogenesis of unilateral cleft lip during postnatal course of the disorder. FOXE1 and BARX1 could be involved with both unilateral and bilateral cleft lip morphopathogenesis. The persistence of MSX2 in all evaluated cleft types could indicate its possible interaction within multiple cleft types. DLX4 most likely is not involved with postnatal cleft morphopathogenesis process.
UNASSIGNED: Nesindrominis veido ir kaukolės nesuaugimas yra santykinai dažna įgimta anomalija, galinti turėti reikšmingų neigiamų pasekmių pediatrinės populiacijos asmenų sveikatos būklei ir gyvenimo kokybei. Aprašyta daugelis genų, kurie potencialiai gali lemti nesuaugimus, ir jų koduojami baltymai, aptariamas galimas jų dalyvavimas susidarant nesuaugimui. Dalis šių baltymų – tokie kaip homeozinis baltymas BarH-tipas 1 (BARX1), distalinis homeozinis genas 4 (DLX4), FOX E1 genas (FOXE1), homeozinis baltymas Hox-B3 (HOXB3) bei raumenų segmento homeozinis 2 genas (MSX2) – buvo siejami su kaukolės ir veido nesuaugimais. Patogeninio nesindrominio kaukolės ir veido nesuaugimo suvokimas galėtų suteikti daugiau žinių, kaip vertinti su nesuaugimais susijusius atvejus bei galimai taptų pradžios tašku, iš kurio kiltų naujos ar tobulesnės nesuaugimo gydymo alternatyvos. Šiame tyrime nagrinėjama, ar yra BARX1, DLX4, FOXE1, HOXB3 ir MSX2 genų turinčių ląstelių, pasitelkiant imunohistochemiją ir nagrinėjant įvairius nesuaugimo paveiktų audinių tipus, siekiant nustatyti galimą jų ryšį su nesuaugimo patogeneze.
UNASSIGNED: Kaukolės ir veido nesuaugimo audinio medžiaga buvo įgyta nesuaugimo korekcinės operacijos metu iš pacientų, kuriems buvo nustatyta nesindrominio kaukolės ir veido nesuaugimo diagnozė. Audinio medžiaga buvo surinkta iš pacientų, kuriems yra vienpusis (n = 36) bei dvipusis lūpos nesuaugimas (n = 13) bei nesuaugęs gomurys (n = 26). Kontrolinės grupės (n = 7) audinio medžiaga gauta iš asmenų, neturinčių jokių kaukolės ar veido nesuaugimų. Teigiamo tyrimo faktoriaus ląstelių skaičius kontrolinės grupės ir pacientų grupės audiniuose buvo vertinamas pusiau kiekybiniu skaičiavimo metodu. Duomenys vertinti pasitelkus neparametrinius statistinius metodus.
UNASSIGNED: Buvo nustatyta statistiškai reikšmingų skirtumų tarp ląstelių, turinčių BARX1, FOXE1, HOXB3 bei MSX2, skaičiaus kontrolinėje grupėje bei pacientų, kurių audinys nesuaugęs, grupėse, tačiau nebuvo nustatyta jokių statistiškai reikšmingų skirtumų dėl DLX4. Statistiškai reikšmingos vertinamų faktorių koreliacijos buvo nustatytos ir pacientų, kurių audiniai nesuaugę, grupėse.
UNASSIGNED: HOXB3 galėtų būti labiau siejamas su vienpusio lūpos nesuaugimo morfopatogeneze po gimimo. FOXE1 ir BARX1 galima raiška tiek vienpusio, tiek ir abipusio lūpos nesuaugimo morfopatogenezėje. Kadangi MSX2 sistemingai yra visų nagrinėjamų nesuaugimo tipų atveju, galima daryti išvadą, kad MSX2 galimai yra susijęs su daugeliu nesuaugimo tipų. DLX4 veikiausiai nėra susijęs su nesuaugimo morfopatogenezės po gimimo procesu.

Homeobox genes serve as master regulatory transcription factors that regulate gene expression during embryogenesis. A homeobox gene may have either tumor-promoting or tumor-suppressive properties depending on the specific organ or cell lineage where it is expressed. The dysregulation of homeobox genes has been reported in various human cancers, including bladder cancer. The dysregulated expression of homeobox genes has been associated with bladder cancer clinical outcomes. Although bladder cancer has high risk of tumor recurrence and progression, it is highly challenging for clinicians to accurately predict the risk of tumor recurrence and progression at the initial point of diagnosis. Cystoscopy is the routine surveillance method used to detect tumor recurrence. However, the procedure causes significant discomfort and pain that results in poor surveillance follow-up amongst patients. Therefore, the development of reliable non-invasive biomarkers for the early detection and monitoring of bladder cancer is crucial. This review provides a comprehensive overview of the diagnostic and prognostic potential of homeobox gene expression dysregulation in bladder cancer.