MEIS-WNT5A axis regulates development of fourth ventricle choroid plexus.

The choroid plexus (ChP) produces cerebrospinal fluid and forms an essential brain barrier. ChP tissues form in each brain ventricle, each one adopting a distinct shape, but remarkably little is known about the mechanisms underlying ChP development. Here, we show that epithelial WNT5A is crucial for determining fourth ventricle (4V) ChP morphogenesis and size in mouse. Systemic Wnt5a knockout, or forced Wnt5a overexpression beginning at embryonic day 10.5, profoundly reduced ChP size and development. However, Wnt5a expression was enriched in Foxj1-positive epithelial cells of 4V ChP plexus, and its conditional deletion in these cells affected the branched, villous morphology of the 4V ChP. We found that WNT5A was enriched in epithelial cells localized to the distal tips of 4V ChP villi, where WNT5A acted locally to activate non-canonical WNT signaling via ROR1 and ROR2 receptors. During 4V ChP development, MEIS1 bound to the proximal Wnt5a promoter, and gain- and loss-of-function approaches demonstrated that MEIS1 regulated Wnt5a expression. Collectively, our findings demonstrate a dual function of WNT5A in ChP development and identify MEIS transcription factors as upstream regulators of Wnt5a in the 4V ChP epithelium.

Disparity of gene expression in coronary artery disease: insights from MEIS1, HIRA, and Myocardin.

INTRODUCTION: Coronary artery disease (CAD) in young adults can have devastating consequences. The cardiac developmental gene MEIS1 plays important roles in vascular networks and heart development. This gene effects on the regeneration capacity of the heart. Considering role of MEIS1 in cardiac tissue development and the progression of myocardial infarction this study investigated the expression levels of the MEIS1, HIRA, and Myocardin genes in premature CAD patients compared to healthy subjects and evaluated the relationships between these genes and possible inflammatory factors. METHODS AND RESULTS: The study conducted a case-control design involving 35 CAD patients and 35 healthy individuals. Peripheral blood mononuclear cells (PBMCs) were collected, and gene expression analysis was performed using real-time PCR. Compared with control group, the number of PBMCs in the CAD group exhibited greater MEIS1 and HIRA gene expression, with fold changes of 2.45 and 3.6. The expression of MEIS1 exhibited a negative correlation with IL-10 (r= -0.312) expression and positive correlation with Interleukin (IL)-6 (r = 0.415) and tumor necrosis factor (TNF)-α (r = 0.534) gene expression. Moreover, there was an inverse correlation between the gene expression of HIRA and that of IL-10 (r= -0.326), and a positive correlation was revealed between the expression of this gene and that of the IL-6 (r = 0.453) and TNF-α (r = 0.572) genes. CONCLUSION: This research demonstrated a disparity in expression levels of MEIS1, HIRA, and Myocardin, between CAD and healthy subjects. The results showed that, MEIS1 and HIRA play significant roles in regulating the synthesis of proinflammatory cytokines, namely, TNF-α and IL-6.

A Comprehensive Analysis of HOXB13 Expression in Hepatocellular Carcinoma.

Background and objectives: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and is caused by multiple factors. To explore novel targets for HCC treatment, we comprehensively analyzed the expression of HomeoboxB13 (HOXB13) and its role in HCC. Materials and Methods: The clinical significance of HCC was investigated using open gene expression databases, such as TIMER, UALCAN, KM, OSlihc, and LinkedOmics, and immunohistochemistry analysis. We also analyzed cell invasion and migration in HCC cell lines transfected with HOXB13-siRNA and their association with MMP9, E2F1, and MEIS1. Results: HOXB13 expression was higher in fibrolamellar carcinoma than in other histological subtypes. Its expression was associated with lymph node metastasis, histological stage, and tumor grade. It was positively correlated with immune cell infiltration of B cells (R = 0.246), macrophages (R = 0.182), myeloid dendritic cells (R = 0.247), neutrophils (R = 0.117), and CD4+ T cells (R = 0.258) and negatively correlated with immune cell infiltration of CD8+ T cells (R = -0.107). A positive correlation was observed between HOXB13, MMP9 (R = 0.176), E2F1 (R = 0.241), and MEIS1 (R = 0.189) expression (p < 0.001). The expression level of HOXB13 was significantly downregulated in both HepG2 and PLC/PFR/5 cell lines transfected with HOXB13-siRNA compared to that in cells transfected with NC siRNA (p < 0.05). Additionally, HOXB13 significantly affected cell viability and wound healing. Conclusions: HOXB13 overexpression may lead to poor prognosis in patients with HCC. Additional in vivo studies are required to improve our understanding of the biological role and the exact mechanism of action of HOXB13 in HCC.

Intraosseous Spindle Cell Rhabdomyosarcoma with MEIS1::NCOA2 Fusion - Case Report with Substantial Clinical Follow-up and Review of the Literature.

Spindle cell/sclerosing rhabdomyosarcoma (SSRMS) is a clinicopathologically and molecularly heterogeneous disease. Gene fusions have been identified in intraosseous SSRMS, consisting predominantly of EWSR1/FUS::TFCP2 and MEIS1::NCOA2. The former often follow an aggressive clinical course; there is limited clinical follow-up available for the latter. We report here a new case of the very rare intraosseous SSRMS with MEIS1::NCOA2 gene fusion and include the detailed treatment course and 52 months of clinical follow-up. SSRMS with MEIS1::NCOA2 gene fusion appears biologically distinct from other intraosseous SSRMS, following a course characterized by local recurrence with rare reports of metastasis to date.

Clinicopathological and Molecular Characteristics of Intraosseous Rhabdomyosarcoma Involving Head and Neck Region: A Systematic Review and Meta-Analysis.

Rhabdomyosarcoma with TFCP2 rearrangement is a newly introduced spindle cell neoplasm showing predilection for craniofacial bones exhibiting highly aggressive nature and poor prognosis. Therefore, an attempt was made to delineate the entity for improved understanding and treatment outcomes through comprehensive analysis of the clinicopathological and molecular characteristics. An electronic search was carried out using MEDLINE by PubMed, Scopus, Google scholar, Cochrane library, and EMBASE databases. Original articles and case reports involving intraosseous rhabdomyosarcoma arising in head and neck region with TFCP2 fusion were included. Data were compiled and risk of bias was analyzed using JBI tool. Thirteen eligible articles were included for the quantitative analysis, which revealed 33 cases with TFCP2 fusion. Majority of the affected individuals were females (58%) with mandible being the common site. Most of the patients died within few months after diagnosis demonstrating a low mean survival rate (30 months). Odds ratio, overall survival and disease-free survival were calculated and analyzed statistically concluding that intraosseous rhabdomyosarcomas harboring TFCP2 fusion are found to be novel and dreadful neoplasms. The predilection for young age with poor prognosis exhibited by these lesions demand early diagnosis and specific treatment planning to curtail mortality.

MEIS1 Is a Common Transcription Repressor of the miR-23a and NORHA Axis in Granulosa Cells.

MicroRNA-23a (miR-23a) is an endogenous small activating RNA (saRNA) involved in ovarian granulosa cell (GC) apoptosis and sow fertility by activating lncRNA NORHA transcription. Here, we reported that both miR-23a and NORHA were repressed by a common transcription factor MEIS1, which forms a small network regulating sow GC apoptosis. We characterized the pig miR-23a core promoter, and the putative binding sites of 26 common transcription factors were detected in the core promoters of both miR-23a and NORHA. Of them, transcription factor MEIS1 expression was the highest in the ovary, and widely distributed in various ovarian cells, including GCs. Functionally, MEIS1 is involved in follicular atresia by inhibiting GC apoptosis. Luciferase reporter and ChIP assays showed that transcription factor MEIS1 represses the transcription activity of miR-23a and NORHA through direct binding to their core promoters. Furthermore, MEIS1 represses miR-23a and NORHA expression in GCs. Additionally, MEIS1 inhibits the expression of FoxO1, a downstream of the miR-23a/NORHA axis, and GC apoptosis by repressing the miR-23a/NORHA axis. Overall, our findings point to MEIS1 as a common transcription repressor of miR-23a and NORHA, and develop the miR-23a/NORHA axis into a small regulatory network regulating GC apoptosis and female fertility.

Homeobox gene Meis1 modulates cardiovascular regeneration.

Regeneration of cardiomyocytes, endothelial cells and vascular smooth muscle cells (three major lineages of cardiac tissues) following myocardial infarction is the critical step to recover the function of the damaged heart. Myeloid ecotropic viral integration site 1 (Meis1) was first discovered in leukemic mice in 1995 and its biological function has been extensively studied in leukemia, hematopoiesis, the embryonic pattering of body axis, eye development and various genetic diseases, such as restless leg syndrome. It was found that Meis1 is highly associated with Hox genes and their cofactors to exert its regulatory effects on multiple intracellular signaling pathways. Recently with the advent of bioinformatics, biochemical methods and advanced genetic engineering tools, new function of Meis1 has been found to be involved in the cell cycle regulation of cardiomyocytes and endothelial cells. For example, inhibition of Meis1 expression increases the proliferative capacity of neonatal mouse cardiomyocytes, whereas overexpression of Meis1 results in the reduction in the length of cardiomyocyte proliferative window. Interestingly, downregulation of one of the circular RNAs, which acts downstream of Meis1 in the cardiomyocytes, promotes angiogenesis and restores the myocardial blood supply, thus reinforcing better regeneration of the damaged heart. It appears that Meis1 may play double roles in modulating proliferation and regeneration of cardiomyocytes and endothelial cells post-myocardial infarction. In this review, we propose to summarize the major findings of Meis1 in modulating fetal development and adult abnormalities, especially focusing on the recent discoveries of Meis1 in controlling the fate of cardiomyocytes and endothelial cells.

Meis1, Hi1α, and GATA1 are integrated into a hierarchical regulatory network to mediate primitive erythropoiesis.

During development, erythroid cells are generated by two waves of hematopoiesis. In zebrafish, primitive erythropoiesis takes place in the intermediate cell mass region, and definitive erythropoiesis arises from the aorta-gonad mesonephros. TALE-homeoproteins Meis1 and Pbx1 function upstream of GATA1 to specify the erythroid lineage. Embryos lacking Meis1 or Pbx1 have weak gata1 expression and fail to produce primitive erythrocytes. Nevertheless, the underlying mechanism of how Meis1 and Pbx1 mediate gata1 transcription in erythrocytes remains unclear. Here we show that Hif1α acts downstream of Meis1 to mediate gata1 expression in zebrafish embryos. Inhibition of Meis1 expression resulted in suppression of hif1a expression and abrogated primitive erythropoiesis, while injection with in vitro-synthesized hif1α mRNA rescued gata1 transcription in Meis1 morphants and recovered their erythropoiesis. Ablation of Hif1α expression either by morpholino knockdown or Crispr-Cas9 knockout suppressed gata1 transcription and abrogated primitive erythropoiesis. Results of chromatin immunoprecipitation assays showed that Hif1α associates with hypoxia-response elements located in the 3'-flanking region of gata1 during development, suggesting that Hif1α regulates gata1 expression in vivo. Together, our results indicate that Meis1, Hif1α, and GATA1 indeed comprise a hierarchical regulatory network in which Hif1α acts downstream of Meis1 to activate gata1 transcription through direct interactions with its cis-acting elements in primitive erythrocytes.

Congenital thrombocytopenia associated with a heterozygous variant in the MEIS1 gene encoding a transcription factor essential for megakaryopoiesis.

The transcription factor MEIS1 (myeloid ectotrophic insertion site 1) is crucial for the maintenance of hematopoietic stem cells and for megakaryopoiesis. Germline variants in MEIS1 are associated with restless-leg syndrome, but were not previously shown to cause cytopenias. This is the first report of a patient with congenital thrombocytopenia associated with a sequence variant in MEIS1, presenting with early onset severe thrombocytopenia and mild signs of bone marrow stress. Whole exome sequencing revealed a de novo monoallelic splice site variant in MEIS1, NM_002398.3:exon4:c.432 + 5 G > C, leading to a premature stop codon. We propose that heterozygous mutations in MEIS1 may cause congenital thrombocytopenia.

The cooperation of cis-elements during M-cadherin promoter activation.

M-cadherin is a skeletal muscle-specific transmembrane protein mediating the cell-cell adhesion of myoblasts during myogenesis. It is expressed in the proliferating satellite cells and highly induced by myogenic regulatory factors (MRFs) during terminal myogenic differentiation. Several conserved cis-elements, including 5 E-boxes, 2 GC boxes, and 1 conserved downstream element (CDE) were identified in the M-cadherin proximal promoter. We found that E-box-3 and -4 close to the transcription initiation site (TIS) mediated most of its transactivation by MyoD, the strongest myogenic MRF. Including of any one of the other E-boxes restored the full activation by MyoD, suggesting an essential collaboration between E-boxes. Stronger activation of M-cadherin promoter than that of muscle creatine kinase (MCK) by MyoD was observed regardless of culture conditions and the presence of E47. Furthermore, MyoD/E47 heterodimer and MyoD ∼ E47 fusion protein achieved similar levels of activation in differentiation medium (DM), suggesting high affinity of MyoD/E47 to E-boxes 3/4 under DM. We also found that GC boxes and CDE positively affected MyoD mediated activation. The CDE element was predicted to be the target of the chromatin-modifying factor Meis1/Pbx1 heterodimer. Knockdown of Pbx1 significantly reduced the expression level of M-cadherin, but increased that of N-cadherin. Using ChIP assay, we further found significant reduction in MyoD recruitment to M-cadherin promoter when CDE was deleted. Taken together, these observations suggest that the chromatin-modifying function of Pbx1/Meis1 is critical to M-cadherin promoter activation before MyoD is recruited to E-boxes to trigger transcription.

The Historical Relationship Between Meis1 and Leukemia.

Acute leukemia (AL) is a poor progressive resistant hematological disease, which has different subtypes and immunophenotypic properties according to leukemic blasts. AL is caused by genetic changes and associated with leukemia stem cells (LSCs), which determine its prognosis and endurance. LSCs are thought to be hematopoietic progenitor and stem cell (HPSCs)-like cells that underwent a malignant transformation. In addition to their low number, LSCs have the characteristics of self-renewal, resistance to chemotherapy, and relapse of leukemia. The myeloid ecotropic integration site-1 (MEIS1) protein is a member of the three-amino acid loop extension (TALE) family of homeodomain (HD) proteins that can bind to DNA sequence-specific manner. Studies have shown that overexpression of MEIS1 and associated cofactors involves tumorigenesis of numerous cancers. Historically, increased expression of Meis1 transcript as well as protein has been determined in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) patients. Moreover, resistance to conventional chemotherapy was observed in leukemic blast samples with high Meis1 content. In this review article, the molecular mechanism of the oncological role of the MEIS1 protein in leukemia and LSC is discussed. In addition, it was suggested that MEIS1 protein could be utilized as a possible treatment target in leukemia with an emphasis on the inhibition of MEIS1, which is overexpressed in LSC.

3D Chromatin Organization Involving MEIS1 Factor in the cis-Regulatory Landscape of GJB2.

The human genome is covered by 8% of candidate cis-regulatory elements. The identification of distal acting regulatory elements and an understanding of their action are crucial to determining their key role in gene expression. Disruptions of such regulatory elements and/or chromatin conformation are likely to play a critical role in human genetic diseases. Non-syndromic hearing loss (i.e., DFNB1) is mostly due to GJB2 (Gap Junction Beta 2) variations and DFNB1 large deletions. Although several GJB2 cis-regulatory elements (CREs) have been described, GJB2 gene regulation remains not well understood. We investigated the endogenous effect of these CREs with CRISPR (clustered regularly interspaced short palindromic repeats) disruptions and observed GJB2 expression. To decipher the GJB2 regulatory landscape, we used the 4C-seq technique and defined new chromatin contacts inside the DFNB1 locus, which permit DNA loops and long-range regulation. Moreover, through ChIP-PCR, we determined the involvement of the MEIS1 transcription factor in GJB2 expression. Taken together, the results of our study enable us to describe the 3D DFNB1 regulatory landscape.

Novel fusion genes in spindle cell rhabdomyosarcoma: The spectrum broadens.

Rhabdomyosarcoma (RMS) encompasses a heterogeneous group of tumors with striated muscle differentiation. RMSs are classified as alveolar, embryonal, spindle cell/sclerosing, and pleomorphic types and molecular analysis of these tumors has identified aberrations that are useful in their further subclassification. Spindle cell rhabdomyosarcoma (SpRMS) is uncommon and has been described with VGLL2 fusions, EWSR1/FUS-TFCP2 rearrangements, and myoD1 mutations-the mutations are associated with significantly different prognoses. In addition, the NCOA2-MEIS1 fusion gene was recently described in two primary intraosseous RMS that contained spindle cell components. Herein, we report three cases of SpRMS harboring different novel fusion genes, one possessing EP300-VGLL3, a second with NCOA2-MEIS1 and CAV1-MET, and the third case had HMGA2-NEGR1 and multiple amplified genes.

The emerging role of MEIS1 in cell proliferation and differentiation.

Cell proliferation and differentiation are the foundation of reproduction and growth. Mistakes in these processes may affect cell survival, or cause cell cycle dysregulation, such as tumorigenesis, birth defects and degenerative diseases, or cell death. Myeloid ecotropic viral integration site 1 (MEIS1) was initially discovered in leukemic mice. Recent research identified MEIS1 as an important transcription factor that regulates cell proliferation and differentiation during cell fate commitment. MEIS1 has a pro-proliferative effect in leukemia cells; however, its overexpression in cardiomyocytes restrains neonatal and adult cardiomyocyte proliferation. In addition, MEIS1 has carcinogenic or tumor suppressive effects in different neoplasms. Thus, this uncertainty suggests that MEIS1 has a unique function in cell proliferation and differentiation. In this review, we summarize the primary findings of MEIS1 in regulating cell proliferation and differentiation. Correlations between MEIS1 and cell fate specification might suggest MEIS1 as a therapeutic target for diseases.

The Small-Molecule Wnt Inhibitor ICG-001 Efficiently Inhibits Colorectal Cancer Stemness and Metastasis by Suppressing MEIS1 Expression.

Recurrence and metastasis remain major obstacles in colorectal cancer (CRC) treatment. Recent studies suggest that a small subpopulation of cells with a self-renewal ability, called cancer stem-like cells (CSCs), promotes recurrence and metastasis in CRC. Unfortunately, no CSC inhibitor has been demonstrated to be more effective than existing chemotherapeutic drugs, resulting in a significant unmet need for effective CRC therapies. In this study, transcriptomic profiling of metastatic tumors from CRC patients revealed significant upregulation in the Wnt pathway and stemness genes. Thus, we examined the therapeutic effect of the small-molecule Wnt inhibitor ICG-001 on cancer stemness and metastasis. The ICG-001 treatment efficiently attenuated self-renewal activity and metastatic potential. Mechanistically, myeloid ecotropic viral insertion site 1 (MEIS1) was identified as a target gene of ICG-001 that is transcriptionally regulated by Wnt signaling. A series of functional analyses revealed that MEIS1 enhanced the CSC behavior and metastatic potential of the CRC cells. Collectively, our findings suggest that ICG-001 efficiently inhibits CRC stemness and metastasis by suppressing MEIS1 expression. These results provide a basis for the further clinical investigation of ICG-001 as a targeted therapy for CSCs, opening a new avenue for the development of novel Wnt inhibitors for the treatment of CRC metastasis.

A Multiplex CRISPR-Screen Identifies PLA2G4A as Prognostic Marker and Druggable Target for HOXA9 and MEIS1 Dependent AML.

HOXA9 and MEIS1 are frequently upregulated in acute myeloid leukemia (AML), including those with MLL-rearrangement. Because of their pivotal role in hemostasis, HOXA9 and MEIS1 appear non-druggable. We, thus, interrogated gene expression data of pre-leukemic (overexpressing Hoxa9) and leukemogenic (overexpressing Hoxa9 and Meis1; H9M) murine cell lines to identify cancer vulnerabilities. Through gene expression analysis and gene set enrichment analyses, we compiled a list of 15 candidates for functional validation. Using a novel lentiviral multiplexing approach, we selected and tested highly active sgRNAs to knockout candidate genes by CRISPR/Cas9, and subsequently identified a H9M cell growth dependency on the cytosolic phospholipase A2 (PLA2G4A). Similar results were obtained by shRNA-mediated suppression of Pla2g4a. Remarkably, pharmacologic inhibition of PLA2G4A with arachidonyl trifluoromethyl ketone (AACOCF3) accelerated the loss of H9M cells in bulk cultures. Additionally, AACOCF3 treatment of H9M cells reduced colony numbers and colony sizes in methylcellulose. Moreover, AACOCF3 was highly active in human AML with MLL rearrangement, in which PLA2G4A was significantly higher expressed than in AML patients without MLL rearrangement, and is sufficient as an independent prognostic marker. Our work, thus, identifies PLA2G4A as a prognostic marker and potential therapeutic target for H9M-dependent AML with MLL-rearrangement.

Deficiency of Meis1, a transcriptional regulator, in mice and worms: Neurochemical and behavioral characterizations with implications in the restless legs syndrome.

Restless legs syndrome is a sleep-related sensorimotor neurological disease affecting up to 10% of the population. Genetic analyses have identified Myeloid Ecotropic viral Integration Site 1 (MEIS1), a transcriptional regulator, to be associated with not only the restless legs syndrome but also self-reported symptoms of insomnia and sleep. This study is to determine if Meis1 deficiency in mice can lead to restless legs syndrome-like phenotypes, and if it is the case, what the underlying mechanisms are. We used two genetic model systems, Caenorhabditis elegans and mice. Egg retention assay and fluorescent reporters were used with C. elegans. For mice, we performed behavioral tests, serum and brain iron detection, qRT-PCR, western blot, immunohistochemistry, and in vitro brain-slice recording. Our results showed that with C. elegans, the function of dop-3, an orthologue of DRD2, was diminished after the knockdown of unc-62, an ortholog of MEIS1. Additionally, unc-62 knockdown led to enhanced transcription of the orthologue of tyrosine hydroxylase, cat-2. Meis1 knockout mice were hyperactive and had a rest-phase-specific increased probability of waking. Moreover, Meis1 knockout mice had increased serum ferritin and altered striatal dopaminergic and cholinergic systems. Specifically, Meis1 knockout mice showed an increased mRNA level but decreased protein level of tyrosine hydroxylase in the striatum. Furthermore, Meis1 knockout mice had increased striatal dopamine turnover and decreased spontaneous firing regularity of striatal cholinergic interneurons. Our data suggest that Meis1 knockout mice have restless legs syndrome-like motor restlessness and changes in serum ferritin levels. The symptoms may be related to dysfunctional dopaminergic and cholinergic systems.

MEIS1 promotes expression of stem cell markers in esophageal squamous cell carcinoma.

BACKGROUND: MEIS1 (Myeloid ecotropic viral integration site 1) as a homeobox (HOX) transcription factor plays regulatory roles in a variety of cellular processes including development, differentiation, survival, apoptosis and hematopoiesis, as well as stem cell regulation. Few studies have established pluripotency and self-renewal regulatory roles for MEIS1 in human esophageal squamous cell carcinoma (ESCC), and our aim in this study was to evaluate the functional correlation between MEIS1 and the stemness markers in ESCC patients and cell line KYSE-30. METHODS: Expression pattern of MEIS1 and SALL4 gene expression was analyzed in different pathological features of ESCC patients. shRNA in retroviral vector was used for constantly silencing of MEIS1 mRNA in ESCC line (KYSE-30). Knockdown of MEIS1 gene and the expression pattern of selected stemness markers including SALL4, OCT4, BMI-1, HIWI, NANOG, PLK1, and KLF4 were evaluated using real-time PCR. RESULTS: Significant correlations were observed between MEIS1 and stemness marker SALL4 in different early pathological features of ESCC including non-invaded tumors, and the tumors with primary stages of progression. Retroviral knockdown of MEIS1 in KYSE-30 cells caused a noteworthy underexpression of both MEIS1 and major involved markers in stemness state of the cells including SALL4, OCT4, BMI-1, HIWI and KLF4. CONCLUSIONS: The results highlight the important potential role of MEIS1 in modulating stemness properties of ESCCs and cells KYSE-30. These findings may confirm the linkage between MEIS1 and self-renewal capacity in ESCC and support probable oncogenic role for MEIS1 in the disease.

Crosstalk between MEIS1 and markers of different cell signaling pathways in esophageal squamous cell carcinoma.

The homeobox transcription factor MEIS1 is involved in cell fate decision, stem cells properties, gastrointestinal (GI) tract development, and progression of several malignancies such as esophageal squamous cell carcinoma (ESCC). Increasing evidences suggest the crosstalk between MEIS1 and cell signaling pathways. Therefore, our aim in present study was to investigate the probable linkage of MEIS1 expression with key genes of different cell signaling pathways in ESCC tumorigenesis, and their correlation with clinicopathological feature of the patients. The gene expression profiling of MEIS1 and different cell signaling genes including SALL4, SIZN1, and HEY1 (stemness state, BMP, and NOTCH signaling pathways, respectively) was performed using quantitative real-time reverse transcription polymerase chain reaction (PCR) in fresh tumoral compared to margin normal tissues of 50 treatment-naive ESCC samples. The mRNA expression of MEIS1/SIZN1, SIZN1/HEY1, and SIZN1/SALL4 were significantly associated to each other (P < 0.05). There were remarkable correlations between concomitant mRNA expression of MEIS1 and SIZN1 in tumors with invasion to adventitia, early stages of tumor progression and poorly differentiated tumors. Moreover, expression of MEIS1 and HEY1 was correlated to each other in primary stages of tumor progression and non-invaded tumors. Expression of MEIS1 was significantly associated with SALL4 in poorly differentiated tumors. Our results indicated that correlation between different cell signaling pathway-related genes may lead to esophageal tumorigenesis. It is illustrated that MEIS1 as a HOX gene has a significant correlation with stemness state, BMP, and NOTCH signaling pathways via the SIZN1.

Mechanisms of Neonatal Heart Regeneration.

PURPOSE OF REVIEW: This review provides an overview of the molecular mechanisms underpinning the cardiac regenerative capacity during the neonatal period and the potential targets for developing novel therapies to restore myocardial loss. RECENT FINDINGS: We present recent advances in the understanding of the molecular mechanisms of neonatal cardiac regeneration and the implications for the development of new cardiac regenerative therapies. During the early postnatal period, several cell types and pathways are involved in cardiomyocyte proliferation including immune response, nerve signaling, extracellular matrix, mitochondria substrate utilization, gene expression, miRNAs, and cell cycle progression. The early neonatal mammalian heart has remarkable regenerative capacity, which is mediated by proliferation of endogenous cardiomyocytes, and is lost when cardiomyocytes stop dividing shortly after birth. A wide array of mechanisms that regulate this regenerative process have been proposed.