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Testicular tumors (TTs) are rare in children, posing diagnostic and therapeutic challenges. This retrospective study evaluates the diagnostic and prognostic utility of SALL4 and OCT3/4 in pediatric TTs. We analyzed 18 cases of different types of TTs using immunohistochemistry (IHC) to assess SALL4 (Spalt-like transcription factor 4) and OCT3/4 (Octamer binding transcription factor 3/4) expression. SALL4 was positive in 83.3% of tumors, while OCT3/4 was positive in 38.9% of tumors, with a significantly higher prevalence in patients aged 12–18 years compared to those aged 0–11 years (p = 0.013). Mixed germinal cell tumors were significantly more frequently associated with OCT3/4 (p = 0.003), and a high immunostaining expression for SALL4 was observed primarily in yolk sac tumors and embryonal carcinoma. Our findings suggest that SALL4 and OCT3/4 immunostaining can aid in accurate diagnosis and treatment planning, and underscores the importance of OCT3/4 as a predictive factor in pediatric testicular tumors, highlighting its substantial correlation with tumor type and its impact on treatment response. These markers may guide personalized therapeutic strategies, potentially improving patient outcomes. [ABSTRACT FROM AUTHOR]

Pediatric ovarian tumors exhibit unique diagnostic and therapeutic challenges. This study evaluates the expression of SALL4 and OCT3/4 biomarkers in pediatric ovarian tumors and their associations with tumor subtype, stage, and clinical outcome. A retrospective analysis was conducted on 64 patients under 18 years old, examining demographic data, tumor characteristics, immunohistochemical staining, and clinical outcomes. Our results show that SALL4 was significantly expressed in adenocarcinoma, dysgerminoma (DSG), mixed germ cell tumors (GCTs), and immature teratoma, while OCT3/4 was highly expressed in DSG and mixed GCTs. Both markers are associated with a higher tumor grade and stage, indicating a more aggressive disease. The SALL4 positivity expression was correlated with high alpha fetoprotein (AFP) and lactate dehydrogenase (LDH) levels, while OCT3/4 positivity significantly predicted the risk of subsequent metastasis. The mean progression-free survival (PFS) was notably shorter in patients with positive markers. These findings underscore the diagnostic and prognostic value of SALL4 and OCT3/4 in pediatric ovarian tumors, aligning with previous research and supporting their use in clinical practice for better disease management and patient outcomes. [ABSTRACT FROM AUTHOR]

Congenital anomalies of the kidney and urinary tract (CAKUT) can be a part of the VACTERL association, which represents the non-random combination of the following congenital anomalies: vertebral anomalies, anal anomalies, cardiac anomalies, tracheal-esophageal anomalies, kidney anomalies, and limb anomalies. VACTERL association is generally considered to be a non-genetic condition. Exceptions include a patient with a heterozygous nonsense SALL4 variant and anal stenosis, tetralogy of Fallot, sacro-vertebral fusion, and radial and thumb anomalies. SALL4 encodes a transcription factor that plays a critical role in kidney morphogenesis. Here, we report a patient with VACTERL association and a heterozygous 128-kb deletion spanning SALL4 who presented with renal hypoplasia, radial and atrio-septal defects, and patent ductus arteriosus. The present report of SALL4 deletion, in addition to a previously reported patient with VACTERL association phenotype and SALL4 nonsense mutation, further supports the notion that SALL4 haploinsufficiency can lead to VACTERL association. [ABSTRACT FROM AUTHOR]

The trunk axial skeleton develops from paraxial mesoderm cells. Our recent study demonstrated that conditional knockout of the stem cell factor Sall4 in mice by TCre caused tail truncation and a disorganized axial skeleton posterior to the lumbar level. Based on this phenotype, we hypothesized that, in addition to the previously reported role of Sall4 in neuromesodermal progenitors, Sall4 is involved in the development of the paraxial mesoderm tissue. Analysis of gene expression and SALL4 binding suggests that Sall4 directly or indirectly regulates genes involved in presomitic mesoderm differentiation, somite formation and somite differentiation. Furthermore, ATAC-seq in TCre; Sall4 mutant posterior trunk mesoderm shows that Sall4 knockout reduces chromatin accessibility. We found that Sall4-dependent open chromatin status drives activation and repression of WNT signaling activators and repressors, respectively, to promote WNT signaling. Moreover, footprinting analysis of ATAC-seq data suggests that Sall4-dependent chromatin accessibility facilitates CTCF binding, which contributes to the repression of neural genes within themesoderm. This study unveils multiple mechanisms by which Sall4 regulates paraxial mesoderm development by directing activation of mesodermal genes and repression of neural genes. [ABSTRACT FROM AUTHOR]

Background: The thalidomide disaster resulted in tremendous congenital malformations in more than 10,000 children in the late 1950s and early 1960s. Summary: Although numerous putative mechanisms were proposed to explain thalidomide teratogenicity, it was confirmed only recently that thalidomide, rather its derivative 5-hydroxythalidomide (5HT) in a complex with the cereblon protein, interferes with early embryonic transcriptional regulation. 5HT induces selective degradation of SALL4, a principal transcriptional factor of early embryogenesis. Genetic syndromes caused by pathogenic variants of the SALL4 gene phenocopy thalidomide embryopathy with congenital malformations ranging from phocomelia, reduced radial ray, to defects of the heart, kidneys, ear, eye, and possibly cerebral midline and pituitary. SALL4 interacts with TBX5 and a handful of other transcriptional regulators and downregulates the Sonic hedgehog signaling pathway. Cranial midline defects, microcephaly, and short stature due to growth hormone deficiency have been occasionally reported in children carrying SALL4 pathogenic variants associated with generalized stunting of growth rather than just the loss of height attributable to the shortening of leg bones in many children with thalidomide embryopathy. Key Messages: Thus, SALL4 joins the candidate gene list for monogenic syndromic pituitary insufficiency. In this review, we summarize the journey from the thalidomide disaster through the functions of the SALL4 gene to its link to the hormonal regulation of growth. [ABSTRACT FROM AUTHOR]

Herein, we report a rare case of a carcinoma with primitive phenotype (enteroblastic and/or hepatoid differentiation) occurring at a colostomy site. The patient was an elderly male who underwent neoadjuvant chemoradiotherapy for rectal cancer, followed by abdominoperineal resection. A biopsy specimen for the rectal carcinoma before neoadjuvant chemoradiotherapy was conventional tubular adenocarcinoma. Moreover, a pathological complete response was confirmed in the proctectomy specimen. However, a colostomy‐site tumor appeared 6 months after the proctectomy, and it was resected 1 year after the initial proctectomy. The colostomy‐site tumor comprised solid to focal glandular growth of atypical polygonal cells with clear to pale eosinophilic cytoplasm and was immunohistochemically positive for cytokeratin, spalt‐like transcription factor 4, glypican‐3, caudal type homeobox 2, and special AT‐rich sequence‐binding protein 2. Thus, the tumor was diagnosed as poorly differentiated adenocarcinoma with primitive phenotype, with suggested origin from the colorectal epithelium. Additionally, a multilocular cystic lesion comprising various types of epithelia was found adjacent to the tumor, suggestive of metaplasia or heterotopia. Changes in the histology and immunophenotype, and the findings of an adjacent cystic lesion suggest a metachronous tumor rather than a recurrence of the primary tumor. [ABSTRACT FROM AUTHOR]

CD44 and SALL4 are markers of stemness and expressed in cancer stem cells (CSCs). Their deregulated expression was seen in various tumors and has been correlated with clinical severity. We evaluated immunohistochemical expression of CD44 and SALL4 in leukoplakia and oral squamous cell carcinoma (OSCC). CD44 was expressed in all the cases of leukoplakia and Its expression correlated with severity of the dysplasia in leukoplakia but varied with differentiation in OSCC. SALL4 did not express in leukoplakia. Its expression was varied in OSCC cases. We opine that CD44 expression is consistent with the progression of dysplasia in leukoplakia and differentiation in OSCC. [ABSTRACT FROM AUTHOR]

Sall1 and Sall4 (Sall1/4), zinc-finger transcription factors, are expressed in the progenitors of the second heart field (SHF) and in cardiomyocytes during the early stages of mouse development. To understand the function of Sall1/4 in heart development, we generated heart-specific Sall1/4 functionally inhibited mice by forced expression of the truncated form of Sall4 (ΔSall4) in the heart. The ΔSall4-overexpression mice exhibited a hypoplastic right ventricle and outflow tract, both of which were derived from the SHF, and a thinner ventricular wall. We found that the numbers of proliferative SHF progenitors and cardiomyocytes were reduced in ΔSall4-overexpression mice. RNA-sequencing data showed that Sall1/4 act upstream of the cyclin-dependent kinase (CDK) and cyclin genes, and of key transcription factor genes for the development of compact cardiomyocytes, including myocardin (Myocd) and serum response factor (Srf). In addition, ChIP-sequencing and co-immunoprecipitation analyses revealed that Sall4 and Myocd form a transcriptional complex with SRF, and directly bind to the upstream regulatory regions of the CDK and cyclin genes (Cdk1 and Ccnbl). These results suggest that Sall1/4 are critical for the proliferation of cardiac cells via regulation of CDK and cyclin genes that interact with Myocd and SRF. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Primary HCO is a rare, aggressive ovarian malignant tumor, morphologically resembling HCC. SALL4 can be adopted to differentiate HCO from HCC. The serum AFP and CA125 rather than HE4 can be employed as possible biomarkers to track treatment and monitor recurrence. We report a case of a postmenopausal woman presenting with lower abdominal pain and vaginal bleeding. She went through a maximal debulking surgery, and the pathological biopsy revealed hepatoid carcinoma of the ovary (HCO). Immunohistochemical assay demonstrates SALL4 as an indicator to differentiate HCO from hepatocellular carcinoma (HCC). [ABSTRACT FROM AUTHOR]

The most common subtype of ovarian carcinoma associated with somatically derived yolk sac tumor (YST) is endometrioid carcinoma. Only two cases of ovarian mucinous carcinomas associated with YST have been reported; herein, we present three additional patients, along with a review of previous literature and our pathology archives to analyze the tumor prognosis. The patients' ages ranged from 38 to 53 years. Two patients had FIGO stage 1 tumors, and one patient had a stage 3 tumor. Two patients died of the disease within a year, and one patient survived with distant metastasis (32 months after surgery). In all three tumors, the YST-like component comprised less than 5% of the total tumor area. Together with the two previously reported mucinous carcinomas with a YST-like component, the prognosis of the five mucinous carcinomas with a YST-like component were compared with that of 19 conventional mucinous carcinomas resected at our hospital. The survival curves were estimated using the Kaplan–Meier method. As a result, the overall survival rate of patients with mucinous carcinomas with a YST-like component was significantly lower than that of patients with conventional mucinous carcinomas (P =.0014). Our study indicates that the presence of a YST-like component in mucinous carcinomas would be a strong prognostic indicator. [ABSTRACT FROM AUTHOR]

Background: Spalt-like protein 4 (SALL4) is a stemness-related transcription factor whose abnormal re-expression contributes to cancer initiation and progression. However, the role of SALL4 in cancer angiogenesis remains unknown. Methods: Analyses of clinical specimens via TCGA datasets were performed to determine the expression level and clinical significance of SALL4 in STAD (Stomach Adenocarcinoma). SALL4 knockdown, knockout, and overexpression were achieved by siRNA, CRISPR/Cas9, and plasmid transfection. The effects of conditioned medium (CM) from SALL4 knockdown or overexpression of gastric cancer cells on endothelial cell proliferation, migration, and tube formation were investigated by CCK-8 assay, transwell migration assay, and tube formation assay. The regulation of VEGF gene expression by SALL4 was studied by qRT-PCR, western blot, chromatin immunoprecipitation (ChIP) assay, and electrophoretic mobility shift assay (EMSA). Engineered exosomes from 293T cells loaded with si-SALL4-B and thalidomide were produced to test their therapeutic effect on gastric cancer progression. Results: SALL4 expression was increased in STAD and positively correlated with tumor progression and poor prognosis. SALL4-B knockdown or knockout decreased while over-expression increased the promotion of human umbilical vein endothelial cells (HUVEC) cell proliferation, migration, and tube formation by gastric cancer cell-derived CM. Further investigation revealed a widespread association of SALL4 with angiogenic gene transcription through the TCGA datasets. Additionally, SALL4-B knockdown reduced, while over-expression enhanced the expression levels of VEGF-A, B, and C genes. The results of ChIP and EMSA assays indicated that SALL4 could directly bind to the promoters of VEGF-A, B, and C genes and activate their transcription, which may be associated with increased histone H3-K79 and H3-K4 modifications in their promoter regions. Furthermore, si-SALL4-B and thalidomide-loaded exosomes could be efficiently uptaken by gastric cancer cells and significantly reduced SALL4-B and Vascular Endothelial Growth Factor (VEGF) expression levels in gastric cancer cells, thus inhibiting the pro-angiogenic role of their derived CM. Conclusion: These findings suggest that SALL4 plays an important role in angiogenesis by transcriptionally regulating VEGF expression. Co-delivery of the functional siRNA and anticancer drug via exosomes represents a useful approach to inhibiting cancer angiogenesis by targeting SALL4/VEGF pathway. [ABSTRACT FROM AUTHOR]

Background: The mechanism involved in prostate cancer (PCa) metastasis is still poorly understood, and several oncogenes are known to regulate this process. However, the role of spalt‐like transcription factor 4 (SALL4) in PCa metastasis remains unclear. Methods: We performed RNA‐sequencing to compare the mRNA expression profiles of seven localized PCa tissues and six metastatic PCa tissues. SALL4 was then identified and compared in the localized PCa and metastatic PCa. Immunohistochemical studies, qRT‐PCR, and Western blot were performed to analyze the expression of SALL4 in PCa patients and cell lines. SALL4 expression and its relevance to clinical traits and prognosis were further explored in the TCGA database and in our 68 clinical samples. Subsequently, we knocked down SALL4 in DU145 and PC3 cells and performed a series of functional assays to explore the effect of SALL4 on PCa progression. Finally, protein levels of SALL4 and core components of the MAPK pathway were measured by Western blot, and cells were treated with PD0325901 to observe proliferation and metastasis. Results: Significantly higher expression of SALL4 was found in metastatic PCa than in localized PCa. In addition, high SALL4 expression was significantly associated with high pathological T stage, N stage, Gleason score, and poor disease‐free survival in TCGA database and in our clinical samples. Functional studies indicated that knockdown of SALL4 in DU145 and PC3 inhibited proliferation, migration, and angiogenesis. Furthermore, the ERK and P38 protein phosphorylation significantly reduced after knockdown of SALL4 in DU145 and PC3, indicating the inactivation of the MAPK signaling pathway. Finally, the proliferation and migration ability of DU145 and PC3 cells were significantly decreased after PD0325901 treatment. Conclusions: SALL4 predicts unfavorable outcome and is closely associated with PCa progression, suggesting that SALL4 may be a promising prognostic marker and potential therapeutic target for PCa. [ABSTRACT FROM AUTHOR]

Background: SALL4 has been demonstrated in many cancers and participated in tumorigenesis and tumor progression, however, its expression and function still remain ambiguous in GC, especially its upstream mechanistic modulators. Purpose: We explored whether the dual mediation of EZH2 and KDM6A could be involved in upstream regulation of SALL4, which promotes GC cell progression via the Wnt/β-catenin pathway. Method: Analysis of discrepant gene expression in GC and normal gastric tissues from The Cancer Genome Atlas (TCGA) dataset. GC cell lines were transfected by siEZH2 and siKDM6A, the transduction molecules of KDM6A/EZH2-SALL4-β-catenin signaling were quantified in the GC cells. Results: Here, we showed that only SALL4 levels of SALL family members were upregulated in nonpaired and paired GC tissues than those in corresponding normal tissues and were associated with its histological types, pathological stages, TNM stages including T stage (local invasion), N stage (lymph node metastasis), M stage (distant metastasis), and overall survival from the TCGA dataset. SALL4 level was elevated in GC cells compared to normal gastric epithelial cell line (GES-1) and was correlated to cancer cell progression and invasion through the Wnt/β-catenin pathway in GC, which levels would be separately upregulated or downregulated by KDM6A or EZH2. Conclusion: We first proposed and demonstrated that SALL4 promoted GC cell progression via the Wnt/β-catenin pathway, which was mediated by the dual regulation of EZH2 and KDM6A on SALL4. This mechanistic pathway in gastric cancer represents a novel targetable pathway. [ABSTRACT FROM AUTHOR]

Laryngeal cancer (LC) is a rare and challenging clinical problem. Our aim was to investigate the mechanism of salt‐like transcription factor 4 (SALL4) in LC. LC tissue and paracancerous tissue were collected. Relative mRNA or protein levels were measured by quantitative real‐time polymerase chain reaction or Western blot. MTT, wound healing, and transwell assay were performed to evaluate cell proliferation, migration and invasion. The binding relationship between SALL4 and USP21 promoter was verified by dual‐luciferase assay and ChIP. Co‐IP and glutathione‐S‐transferase (GST)‐pull down were performed to measure the protein interaction between USP21 and YY1. Additionally, YY1 ubiquitination level was analyzed. It was found that SALL4 mRNA and SALL4 protein levels were elevated in LC clinical tissues and various LC cells. Knockdown of SALL4 inhibited epithelial–mesenchymal transition (EMT) of LC cells. USP21 was transcriptionally activated by SALL4. Co‐IP and GST‐pull down confirmed USP21 interacted with YY1. USP21 protected YY1 from degradation through deubiquitination. Furthermore, overexpression of USP21 reversed the effect of knockdown of SALL4 on YY1 and EMT in LC cells. In general, SALL4 facilitated EMT of LC cells through modulating USP21/YY1 axis. [ABSTRACT FROM AUTHOR]

The utilization of cardiac progenitor cells (CPCs) has been shown to induce favorable regenerative effects. While there are various populations of endogenous CPCs in the heart, there is no consensus regarding which population is ideal for cell-based regenerative therapy. Early-stage progenitor cells can be differentiated into all cardiovascular lineages, including cardiomyocytes and endothelial cells. Identifying an Islet-1+ (Isl-1+) early-stage progenitor population with enhanced stemness, multipotency and differentiation potential would be beneficial for the development of novel regenerative therapies. Here, we investigated the transcriptome of human neonatal Isl-1+ CPCs. Isl-1+ human neonatal CPCs exhibit enhanced stemness properties and were found to express Spalt-like transcription factor 4 (SALL4). SALL4 plays a role in embryonic development as well as proliferation and expansion of hematopoietic progenitor cells. SALL4, SOX2, EpCAM and TBX5 are co-expressed in the majority of Isl-1+ clones isolated from neonatal patients. The pre-mesendodermal transcript TFAP2C was identified in select Isl-1, SALL4, SOX2, EpCAM and TBX5 expressing clones. The ability to isolate and expand pre-mesendodermal stage cells from human patients is a novel finding that holds potential value for applications in regenerative medicine. [ABSTRACT FROM AUTHOR]

SALL4 transcription factor plays an important role to maintain the pluripotent and self‐renewal of embryonic stem cells. It contributes to the growth of many cancers and embryonic development. With the exception of spermatogonia, SALL4 expression is silenced in most adult tissues after birth; nevertheless, it is re‐expressed in a subset of different solid malignancies. SALL4 is a new, precise biomarker for testicular germ cell cancers that was just introduced. The whole isoform of SALL4 is called SALL4‐A. Regarding the lack of antibody against human SALL4 isoforms, the pattern of expression, the role of each isoform remain unknown. Furthermore, in isoform specific evaluations, we aimed, for the first time, to produce and characterize mAb against human SALL4‐A. Immunization of mice were performed with a selected 33‐mer synthetic peptide of SALL4‐A conjugated with KLH. Hybridoma cells were screened by ELISA for positive reactivity with SALL4‐A peptide. From the ascites fluid of mice that had been injected with hybridoma cells, anti‐SALL4‐A mAbs were isolated using a protein G column. Reactivity of the mAbs was evaluated using the peptide and SALL4‐A recombinant protein by ELISA and IHC on testicular cancer tissue as positive control, and normal kidney, stomach and prostate tissues as negative control. The produced mAb could well detect SALL4‐A in testicular cancer tissues using IHC, while the reactivity was negative in normal kidney, stomach and prostate tissues. Using ELISA, the mAb affinity for the peptide and SALL4‐A recombinant protein was assessed, and it was shown to be reasonably high. The mAb detected SALL4‐A in nucleus and cytoplasm of several cancer cells and spermatogonia in testicular cancer tissue. In addition, it could recognize SALL4‐A recombinant protein. Our produced monoclonal antibody against isoform‐A of human SALL4 can specifically recognize SALL4‐A using either IHC or ELISA. We hope that this mAb could help researchers in isoform‐specific study of human SALL4. [ABSTRACT FROM AUTHOR]

Treatment for the HER2+ breast cancer subtype is still unsatisfactory, despite breakthroughs in research. The discovery of various new molecular mechanisms of transcription factors may help to make treatment regimens more effective. The transcription factor SALL4 has been related to aggressiveness and resistance therapy in cancer. Its molecular mechanisms and involvement in various signaling pathways are unknown in the HER2+ breast cancer subtype. In this study, we have evaluated the implication of SALL4 in the HER2+ subtype through its expression in patients' samples and gain and loss of function in HER2+ cell lines. We found higher SALL4 expression in breast cancer tissues compared to healthy tissue. Interestingly, high SALL4 expression was associated with disease relapse and poor patient survival. In HER2+ cell lines, transient overexpression of SALL4 modulates PI3K/AKT signaling through regulating PTEN expression and BCL2, which increases cell survival and proliferation while reducing the efficacy of trastuzumab. SALL4 has also been observed to regulate the epithelial–mesenchymal transition and stemness features. SALL4 overexpression significantly reduced the epithelial markers E-cadherin, while it increased the mesenchymal markers β-catenin, vimentin and fibronectin. Furthermore, it has been also observed an increased expression of MYC, an essential transcription factor for regulating epithelial-mesenchymal transition and/or cancer stem cells. Our study demonstrates, for the first time, the importance of SALL4 in the HER2+ subtype and partial regulation of trastuzumab sensitivity. It provides a viable molecular mechanism-driven therapeutic strategy for an important subset of HER2-overexpressing patients whose malignancies are mediated by SALL4 expression. [ABSTRACT FROM AUTHOR]

p53 plays a pivotal role in maintaining the genomic stability of mouse embryonic stem cells (mESCs) through transcriptionally activating and repressing target genes. However, how p53 recognizes its repressed targets remains largely unknown. Herein, we demonstrate that Sall4 negatively regulates DNA damage induced apoptosis (DIA) of mESCs through mediating p53 recruitment to enhancers of ESC-associated genes repressed by p53 from promoters of p53-activated genes. Upon DNA damage, Sall4 is transcriptionally repressed by p53 and plays an anti-apoptotic role without altering p53 activation. Moreover, Sall4 is identified as a novel p53-interacting partner. Consistently, Sall4 exerts its anti-apoptotic function in a p53-dependent manner. Intriguingly, Sall4 depletion not only promotes the transcriptional activation of several p53-regulated pro-apoptotic genes but also compromises p53-mediated repression of ESC master transcription factors in response to DNA damage. Mechanistically, Sall4 balances p53-binding affinity between p53-activated and -repressed genes through tethering p53 to ESC enhancers. In light of our study, Sall4 may contribute to tumorigenesis by antagonizing p53-mediated apoptosis. [ABSTRACT FROM AUTHOR]

Spalt-Like Transcription Factor 4 (SALL4) is a critical factor for self-renewal ability and pluripotency of stem cells. On the other hand, various reports show tight relation of SALL4 to cancer occurrence and metastasis. SALL4 exerts its effects not only by inducing gene expression but also repressing a large cluster of genes through interaction with various epigenetic modifiers. Due to high expression of SALL4 in cancer cells and its silence in almost all adult tissues, it is an ideal target for cancer therapy. However, targeting SALL4 meets various challenges. SALL4 is a transcription factor and designing appropriate drug to inhibit this intra-nucleus component is challenging. On the other hand, due to lack of our knowledge on structure of the protein and the suitable active sites, it becomes more difficult to reach the appropriate drugs against SALL4. In this review, we have focused on approaches applied yet to target this oncogene and discuss the potential of degrader systems as new therapeutics to target oncogenes. [ABSTRACT FROM AUTHOR]

HAC is a rare extrahepatic malignancy histologically resembling hepatocellular carcinoma which can occur in many organs. Especially for cases carrying HAC within the stomach or duodenum, we found that typically HAC only happened in either of them and there was no case exhibiting HAC in both sites. Here, we presented a case having HAC in both sites and to our knowledge, this is the first report presenting HAC in these two distinct organs simultaneously. Firstly, a 57-year-old male was tested for increased serum alpha-fetoprotein level. Following PET-CT images showed strengthened FDG uptake in the gastric antrum and proximal duodenum. Esophagogastroduodenoscopy also revealed an irregular lump at the gastric antrum and a deep ulceration at the duodenum bulb. Next, an immunohistochemistry panel confirmed the diagnosis of HAC. Finally, genetic tests were performed on this patient after the clinical diagnosis of HAC to reveal the molecular etiology. [ABSTRACT FROM AUTHOR]

Carcinosarcoma of the stomach is a rare neoplasm characterized by the presence of both epithelial and mesenchymal malignant components. We describe four examples with a focus on the characterization of the epithelial components and the histogenetic implications for this unique tumor. All patients were men aged 40–79 years. All patients developed metastatic disease, and three of them died 4–19 months after the diagnosis. Sarcomatous elements included poorly differentiated spindle cell sarcoma without distinctive differentiation (n = 4), chondrosarcoma (n = 2), and rhabdomyosarcoma (n = 1). In two cases, the sarcomatous component was recognized only in metastatic lesions. Notably, carcinomatous components were characterized by multilineage and primitive cellular differentiation, including carcinoma with enteroblastic (n = 4), hepatoid (n = 3), yolk sac tumor-like (n = 1), trophoblastic (n = 1), and neuroendocrine (n = 1) differentiation, as well as conventional tubular adenocarcinoma (n = 4). On immunohistochemistry, all four cases showed varying degrees of positive expression of primitive phenotypic markers, including alpha-fetoprotein (AFP), glypican-3, or SALL4. All tumors showed mutant patterns of p53 staining, exhibiting either diffusely positive or completely negative staining. On the basis of these findings, at least some gastric carcinosarcomas are likely to be derived from carcinoma with a primitive phenotype, including AFP-producing adenocarcinoma. Our observations suggest that sarcomatous differentiation, as well as multilineage differentiation of epithelial components, may represent increased cellular plasticity of gastric carcinoma with a primitive phenotype. [ABSTRACT FROM AUTHOR]

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Background: Spalt-like transcription factor 4 (SALL4) and aldehyde dehydrogenase1 family member A1 (ALDH1A1) expressing cells have been characterized as possessing stem cell-like properties known as cancer stem cell marker in serous ovarian carcinoma (SOC). Methods: The association between SALL4 and ALDH1A1 was observed based on literature review and bioinformatics tools. Therefore, this study aimed to investigate the association between the co-expression of SALL4/ALDH1A1 proteins and clinicopathological parameters and their prognostic value in SOC patients using immunohistochemical staining on tissue microarrays (TMAs). Furthermore, benign tumors and normal tissue samples were compared with the expression of the tumor tissue samples. Results: Increased co-expression of SALL4/ALDH1A1 was found to be significantly associated with the advanced FIGO stage (P = 0.047), and distant metastasis (P = 0.028). The results of Kaplan–Meier survival analysis indicated significant differences between disease- specific survival (DSS; P = 0.034) or progression-free survival (PFS; P = 0.018) and the patients with high and low co-expression of SALL4/ALDH1A1, respectively. Furthermore, high level co-expression of SALL4/ALDH1A1 was a significant predictor of worse DSS and PFS in the univariate analysis. The data also indicated that the co-expression of SALL4/ALDH1A1 was an independent prognostic factor affecting PFS. Moreover, the co-expression of SALL4/ALDH1A1 added prognostic values of DSS in patients with SOC who had grade III versus grade I in multivariate analysis. Conclusions: Our data demonstrated that high co-expression of SALL4/ALDH1A1 was found to be significantly associated with tumor aggressiveness and worse DSS or PFS in SOC patients. Therefore, co-expression of SALL4/ALDH1A1 may serve as a potential prognostic biomarker of cancer progression in these cases. [ABSTRACT FROM AUTHOR]

Copyright of Patologia Revista Latinoamericana is the property of Asociacion Latinoamericana de Patologia/Asociacion Mexicana de Patologia/Consejo Mexicano de Medicos and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Practical Oncology Journal is the property of Journal of Practical Oncology Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Accumulating evidence suggested that many long noncoding RNAs (lncRNAs) were widely involved in the development and progression of non-small cell lung cancer (NSCLC). However, the roles of lncRNA homeobox A11 antisense (HOXA11-AS) and its underlying mechanism in NSCLC remains largely unknown. The expression levels of HOXA11-AS, miR-3619-5p and sal-like protein 4 (SALL4) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot analysis was used to measure the protein levels of hexokinase II (HK2) and SALL4. Cell proliferation, apoptosis, migration and invasion were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry and transwell assay, respectively. The glucose consumption and lactate production were measured using glucose assay kit and lactate assay kit, respectively. The potential binding sites between miR-3619-5p and HOXA11-AS or SALL4 were predicted by online software and verified by luciferase report assay. A xenograft tumor model was established to confirm the function of HOXA11-AS in NSCLC in vivo. HOXA11-AS and SALL4 were upregulated while miR-3619-5p was downregulated in NSCLC tissues and cells. HOXA11-AS knockdown suppressed cell proliferation, migration, invasion, and glycolysis but promoted apoptosis in NSCLC cells. Moreover, miR-3619-5p could directly bind to HOXA11-AS and its inhibition attenuated the inhibitory effect of HOXA11-AS knockdown on progression of NSCLC cells. Furthermore, SALL4 was a direct target of miR-3619-5p and its overexpression reversed the anti-tumor role of miR-3619-5p in NSCLC cells. Besides, HOXA11-AS modulated SALL4 expression via sponging miR-3619-5p. Additionally, silencing HOXA11-AS inhibited tumor growth though upregulating miR-3619-5p and downregulating SALL4. Collectively, HOXA11-AS knockdown inhibited the progression of NSCLC by regulating miR-3619-5p/SALL4 axis, which might offer a novel avenue for interpreting the mechanism of NSCLC development. [ABSTRACT FROM AUTHOR]

Background: Certain gastric cancers exhibit some primitive phenotypes, which may indicate a high malignancy. In histologically differentiated early gastric cancer (EGC), the presence and the clinicopathological significance of the primitive phenotype remain unclear. Methods: Using immunohistochemical staining we detected the expression of three primitive phenotypic markers SALL4, Glypican-3(GPC3), and AFP in whole tissue sections of differentiated EGC (gastrectomy specimens, n = 302). For those cases with primitive phenotypes, we analyzed their clinicopathological features and evaluated whether the criteria for endoscopic resection were met. Results: We found that 9.3% (28/302) of all differentiated EGC cases have primitive phenotypes, and most of these cases (25/28) exhibit a histomorphology similar to conventional differentiated EGC. Patients with primitive phenotypes had a deeper invasion, a higher rate of ulcer and lymphatic invasion than cases without primitive phenotype. Moreover, patients with primitive phenotypes displayed a significantly higher frequency of LNM than those without (57.1% vs 8.8%, P < 0.001). Multivariate analysis revealed that presence of primitive phenotypes was an independent risk factor for LNM (P = 0.001, HR 6.977, 95% CI: 2.199–22.138). Interestingly, we found 2 cases with primitive phenotypes developed LNM, and they both met the expanded indications of endoscopic resection for differentiated EGC. Conclusions: A small number of differentiated EGC have primitive phenotypes, which were closely related to LNM and were an independent risk factor for LNM. Given its highly aggressive behavior, differentiated EGC with primitive phenotypes should be evaluated with stricter criteria before endoscopic resection, or considered to give an additional surgical operation after endoscopic resection. [ABSTRACT FROM AUTHOR]

Stemness is now an accepted cause of treatment failure and relapse in cancer patients. Laryngeal squamous cell carcinoma patients face a high recurrence and metastatic disease. Research efforts have focused in recent years on discovering biomarkers of poor prognosis in laryngeal cancer patients. SALL4 is an embryonic stem cell factor which has been reported to be highly expressed; and to play a role in oncogenesis and progression in several malignant tumours. As of yet, the expression of this protein has not been assessed in laryngeal cancer. This study provides evidence of positive expression of this protein in laryngeal cancer cells, with positive correlation in the same tumour cells with a second stemness agent, CD 44. Furthermore, it discusses the shared pathways between the two proteins in EMT, Wnt pathway and stemness phenomenon; and proposes further studies to elucidate the role of this protein in laryngeal squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the expression of spalt like transcription factor 4 (SALL4) in the three most common types of renal cell carcinomas (RCC) [clear cell RCC (ccRCC), papillary renal cell carcinoma (pRCC) and chromophobe RCC (chRCC)], and the association with the overall survival (OS) of patients. The Cancer Genome Atlas (TCGA) database and RCC samples were used to investigate the expression levels of the SALL4 gene and its association with the OS in the three types of RCC based on the analysis of the transcriptome, copy number and survival data. It was found that SALL4 was highly expressed in ccRCC and pRCC tumor tissue, and low mRNA expression level of SALL4 indicated a prolonged survival in both ccRCC and pRCC. This mRNA expression level was associated with pathological Tumor-Node-Metastasis stage, M and T stages in both ccRCC and pRCC. The analysis of the enriched pathway results suggested that SALL4 may act via translation initiation, and that the related genes promoted the progression of RCC. Moreover, the high expression level of SALL4 was detected in RCC samples and serum from patients. It was demonstrated that SALL4 promotes increased viability in RCC cells. Therefore, the present results suggest that SALL4 may be a sensitive and specific cancer biomarker in ccRCC and pRCC. Furthermore, targeting of SALL4 may improve RCC therapy and prolong the survival of patients with ccRCC or pRCC. [ABSTRACT FROM AUTHOR]

Background: Sal-like protein 4 (SALL4), an embryonic stem cell factor, has been reported to play an essential role in embryogenesis and oncogenesis. As yet, however, the expression and role of this transcription factor in head and neck squamous cell carcinoma (HNSCC) has not been established. Methods: We assessed SALL4 mRNA expression in a well-characterised dataset of 230 HNSCC samples (test cohort 110 cases and validation cohort 120 cases). We also transfected HNSCC cells (FaDu and UM-SCC-6) with SALL4 siRNA and assessed its effects on proliferation and expression of specific epigenetic factors in order to uncover the role of SALL4 in HNSCC. Results: Overexpression of SALL4 was detected in tumour samples of both cohorts. HNSCC cells treated with SALL4 siRNA showed a reduction in growth and a decrease in DNA methyltransferase 3 alpha (DNMT3A) expression. In the patient cohorts, SALL4 overexpression was found to significantly correlate with disease recurrence (p < 0.001) and SALL4 methylation status (p = 0.002). We also found that DNMT3A was significantly upregulated upon SALL4 upregulation (p < 0.001). High expression levels of SALL4 correlated with decreases in disease-free survival (DFS) rates (log-rank test, p < 0.001). Multivariate analysis revealed that SALL4 expression served as an independent prognostic factor for DFS (hazard ratio: 2.566, 95% confidence interval: 1.598–4.121; p < 0.001). Conclusions: Our findings indicate that SALL4 upregulation correlates with HNSCC tumour aggressiveness and an adverse patient outcome. Our findings also indicate that DNMT3A may synergistically contribute to the regulatory effects of SALL4. Our findings provide insight into SALL4-mediated HNSCC development via epigenetic modulation. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is malignant cancer that threatens the health of millions of females worldwide. Long non-coding RNA (lncRNA) small nucleolar RNA host gene 12 (SNHG12) has been identified as an oncogene in multiple cancers. However, the regulatory role of SNHG12 in BC cell progression is still obscured. The levels of SNHG12, miR-15a-5p, and Sal-like 4 (SALL4) in BC tumor tissues and cells were measured by qRT-PCR. Cell viability, apoptosis, migration, and invasion were examined by CCK8, flow cytometry, and transwell assay, respectively. The interaction between miR-15a-5p and SNHG12 or SALL4 was evaluated by dual-luciferase reporter assay. Protein expression of SALL4 was analyzed by western blot. Xenograft mice were established by subcutaneously injecting BC cells stably transfected with sh-SNHG12 and sh-NC. SNHG12 and SALL4 expressions were upregulated whereas miR-15a-5p was downregulated in BC tumors compared with normal tissues. Besides, miR-15a-5p was correlated with SNHG12 and SALL4 inversely as calculated by Pearson's correlation coefficient. More importantly, SNHG12 knockdown attenuated BC tumor growth in vitro and in vivo. Subsequently, dual-luciferase reporter assay confirmed the interaction between miR-15a-5p and SNHG12 or SALL4. The rescue experiments revealed that miR-15a-5p inhibitor restored SNHG12 silencing induced inhibition on BC cell proliferation, migration, invasion, and promotion of apoptosis. Additionally, SNHG12 was found to accelerate BC cell progression by absorbing miR-15a-5p to enhance SALL4 expression. SNHG12 promotes cell proliferation, migration, and invasion but suppresses apoptosis in BC by upregulating SALL4 expression via sponging miR-15a-5p, representing potential targets for the development of novel diagnosis and treatment methods. [ABSTRACT FROM AUTHOR]

Background: Although ongoing development of therapeutic strategies contributes to the improvements in clinical management, clear cell renal cell carcinoma (ccRCC) deaths originate mainly from radiochemoresistant and metastatic disease. Transcription factor SALL4 has been implicated in tumorigenesis and metastasis of multiple cancers. However, it is not known whether SALL4 is involved in the pathogenesis of ccRCC. Methods: Analyses of clinical specimen and publicly available datasets were performed to determine the expression level and clinical significance of SALL4 in ccRCC. The influence of SALL4 expression on ccRCC tumor growth, metastasis and vascularity was evaluated through a series of in vitro and in vivo experiments. Western blotting, immunofluorescence staining and integrative database analysis were carried out to investigate the underlying mechanism for SALL4-mediated oncogenic activities in ccRCC. Results: SALL4 expression was increased in ccRCC and positively correlated with tumor progression and poor prognosis. SALL4 could promote ccRCC cell proliferation, colony formation, cell cycle progression, migration, invasion and tumorigenicity and inhibit cell senescence. Further investigation revealed a widespread association of SALL4 with individual gene transcription and the involvement of SALL4 in endothelium development and vasculogenesis. In the context of ccRCC, SALL4 promoted tumor vascularization by recruiting endothelial cells. In addition, we found that SALL4 could exert its tumor-promoting effect via modulating Akt/GSK-3β axis and VEGFA expression. VHL mutation and DNA hypomethylation may be involved in the upregulation of SALL4 in ccRCC. Conclusions: Overall, our results provide evidence that upregulated SALL4 can function as a crucial regulator of tumor pathogenesis and progression in ccRCC, thus offering potential therapeutic strategies for future treatment. [ABSTRACT FROM AUTHOR]

Background: SALL4 is a zinc finger transcription factor that exerts its physiological role during embryo-fetal development. Analyses of SALL4 expression have shown its oncogenic role in precursor B-cell lymphoblastic lymphoma, acute and chronic myeloid leukemia, gastrointestinal, breast, and lung cancers. The aim of this study was to determine the immunohistochemical profile of SALL4 in pediatric yolk sac tumors (YSTs).Methods and Results: Immunohistochemistry detection of SALL4 was performed in 22 cases of pediatric YSTs and 10 mature teratomas. The percentage of tumor cells stained was scored as 0, 1+ (1-30% cells), 2+ (31-60%), 3+ (61-90%), and 4+ (> 90%). To compare its sensitivity and specificity with Glypican-3 and α-fetoprotein (AFP), we also stained tumors from these cases for Glypican-3 and AFP. In contrast to AFP and glypican-3, SALL4 staining in more than 90% of the tumor cells was seen in all 22 pediatric YSTs (100% sensitivity) (P < 0.001 for both SALL4 vs. AFP and SALL4 vs. glypican-3).Conclusions: SALL4 is a sensitive marker for pediatric YSTs and it can be used to distinguish them from mature teratomas. SALL4 is likely to become a new and valuable biomarker for the diagnosis of pediatric YST. [ABSTRACT FROM AUTHOR]

Background: The stem cell factor SALL4 is reactivated in human cancers. SALL4 plays diverse roles in tumor growth, metastasis, and drug resistance, but its role in tumor metabolism has not been well characterized. Methods: The glycolytic levels of gastric cancer cells were detected by glucose uptake, lactate production, lactate dehydrogenase activity, ATP level, and hexokinase activity. QRT-PCR and western blot were used to detect the changes in the expression of glycolytic genes and proteins. The downstream target genes of SALL4 were identified by microarray. The regulation of hexokinase II (HK-2) by SALL4 was analyzed by luciferase reporter assay and chromatin immunoprecipitation assay. Transwell migration assay, matrigel invasion assay, cell counting assay and colony formation assay were used to study the roles of HK-2 regulation by SALL4 in gastric cancer cells in vitro. The effects of SALL4 on glycolysis and gastric cancer progression in vivo were determined by subcutaneous xenograft and peritoneal metastasis tumor models in nude mice. Results: SALL4 knockdown inhibited glucose uptake, lactate production, lactate dehydrogenase activity, ATP level and hexokinase activity in gastric cancer cells, and decreased the expression of glycolytic genes and proteins. Microarray analysis showed that SALL4 knockdown affected glycolysis-related pathway. The regulation of HK-2 gene expression by SALL4 was confirmed by luciferase reporter assay and chromatin immunoprecipitation assay. HK-2 knockdown abrogated the promotion of glycolysis by SALL4 in gastric cancer cells, indicating that HK-2 acts as a downstream effector of SALL4. Moreover, HK-2 knockdown reversed the promoting role of SALL4 in gastric cancer cell proliferation, migration and invasion, suggesting that SALL4 drives gastric cancer progression by upregulating HK-2. Conclusions: SALL4 promotes gastric cancer progression through HK-2-mediated glycolysis, which reveals a new mechanism for the oncogenic roles of SALL4 in cancer. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background In acute myeloid leukemia (AML), many genes have been studied as prognostic markers. SALL4 is expressed constitutively in human leukemia cell lines and primary AML cells. BMI-1 is expressed highly in purified hematopoietic stem cells (HSCs), and its expression declines with differentiation. Objective To study the expression levels of SALL4 and BMI-1 and their clinical significance in patients with AML. Methods The study was performed with 60 patients newly diagnosed with AML and 50 control individuals. SALL4 and BMI-1 expression detection were performed using real-time polymerase chain reaction (PCR). Results The expression of SALL4 and BMI-1 was significantly higher in cases of AML and showed a strong association with failure to achieve complete remission (CR) or with relapse (P =.02, P =.03, respectively). In multivariate analysis, these genes were the most powerful independent predictors of poor prognosis (P =.01 for SALL4 , P =.02 for BMI-1). Conclusion SALL4 and BMI-1 are significant prognostic factors in AML and could be strong targets for novel types of therapy. [ABSTRACT FROM AUTHOR]

Alpha-fetoprotein (AFP)-producing gastric carcinomas (AFPGCs) are relatively rare tumors known to have a poor prognosis and commonly found as advanced lesions. Histologically, AFPGCs have been described as having hepatoid and fetal enteric (enteroblastic) morphology and are associated with conventional adenocarcinomas. Prior studies reported a hepatoid component present only in invasive areas and hypothesized that AFPGCs may develop hepatoid features during the process of tumor invasion. We report three cases of AFP-producing early gastric cancer which had an intramucosal hepatoid component. Immunohistochemistry showed that the hepatoid component was diffusely immunoreactive for SALL4, AFP, arginase-1, and HepPar1, and focally for CDX2 and PDX1. An intramucosal transition between the hepatoid component and conventional intramucosal adenocarcinoma was identified. Two patients also had a coexistent fetal enteric component, which was admixed with a hepatoid component. Although at an early stage one patient subsequently developed liver metastasis and a second patient was suspected of having liver metastasis, these were not biopsy-proven. The latter patient had a previous history of hepatocellular carcinoma (HCC) and SALL4 was used on the HCC to distinguish metastatic/further HCC from a gastric metastatic primary with hepatoid differentiation. [ABSTRACT FROM AUTHOR]

Problem: To investigate EMT phenotype and SALL4 expression of circulating tumour cells (CTCs) in patients with gestational trophoblastic neoplasm (GTN). Method of study: CanPatrol CTC detection system in combination with SALL4 RNA in situ hybridization was used to investigate the profile of CTCs in different types of gestational trophoblastic disease (GTD). Circulating CTCs were phenotyped and annotated with SALL4 expression in 41 GTD patients, including 12 HM and 29 GTN, as well as 22 pregnant volunteers. Results: A positive correlation between the number of CTC and serum β‐hCG concentration was found among the GTN patients. The number of E/M‐CTC was positively correlated with serum β‐hCG, while M‐CTC was positively correlated with prognostic score. Comparison among malignant GTD, benign GTD and healthy pregnant women revealed a significant difference in the number of total CTC, E/M‐CTC, and M‐CTC but not in E‐CTC. ROC analysis was conducted to evaluate the performance of CTC phenotypes in distinguishing GTD patients from healthy pregnant women yielding an AUC as 0.826. Youden's index was maximal at the cutoff value of 8.5/4 mL with sensitivity and specificity at 53.66% and 100%, respectively. SALL4 expression was evaluated in GTD patients with CTC count greater than cutoff value. SALL4 high expressing CTCs (>2 signal dots) were detected in 66.67% (10/15) of malignant GTD patients but not in benign patients (0/5). Conclusion: Differential expression of SALL4 was seen in CTCs derived from hydatidiform moles and GTN. CTC profiling may be developed as an adjunct marker to diagnose GTN. [ABSTRACT FROM AUTHOR]

Extragonadal germ cell tumors (EGGCTs) are uncommon neoplasms, which arise in anatomical locations other than gonads. The pathogenesis of these neoplasms is still poorly understood and it is a matter of debate if they really represent extragondal primary neoplasms or rather extragondal metastasis from occult gonadal neoplasms. The actual observations suggest that EGGCTs represent a unique entity, so their biology and behavior are substantially different from gonadal counterparts. The diagnosis of EGGCTs is often challenging, and differential diagnosis is particularly wide. Nevertheless, a correct diagnosis is essential for the correct management of the patient. We summarize the state of art about EGGCTs, with particular emphasis on diagnosis and prognosis. [ABSTRACT FROM AUTHOR]

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SALL4 is overexpressed in many cancers and is found to be involved in tumorigenesis and tumor progression. However, the function of SALL4 in cervical cancer remains unknown. Here, we showed that the expression of SALL4 was gradually increased from normal cervical tissue to high‐grade squamous intraepithelial lesions and then to squamous cervical carcinoma. SALL4 was upregulated or downregulated in cervical cancer cells by stably transfecting a SALL4‐expressing plasmid or a shRNA plasmid targeting SALL4, respectively. In vitro, cell growth curves and MTT (3‐(4,5‐dimethylthiazole‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assays showed that SALL4 promoted the cell proliferation of cervical cancer cells. In vivo, xenograft experiments verified that SALL4 enhanced the tumor formation of cervical cancer cells in female BALB/c Nude mice. Cell cycle analysis by fluorescence‐activated cell sorting found that SALL4 accelerates cell cycle transition from the G0/G1 phase to the S phase. TOP/FOP‐Flash reporter assay revealed that SALL4 significantly upregulates the activity of Wnt/β‐catenin pathway. Western blotting showed that the expression levels of β‐catenin and important downstream genes, including c‐Myc and cyclin D1, were increased by SALL4 in cervical cancer cells. Furthermore, dual‐luciferase reporter and chromatin immunoprecipitation assays confirmed that SALL4 transcriptionally activated CTNNB1 by physically interacting with its promoters. Taken together, The results of this study demonstrated that SALL4 may promote cell proliferation and tumor formation of cervical cancer cells by upregulating the activity of the Wnt/β‐catenin signaling pathway by directly binding to the CTNNB1 promoter and trans‐activating CTNNB1. [ABSTRACT FROM AUTHOR]

Zinc‐finger protein 384 (ZNF384) fusion (Z‐fusion) genes have recently been identified as recurrent fusion genes in B‐cell precursor acute lymphoblastic leukaemia (BCP‐ALL) and have been detected in 7–17% of Philadelphia chromosome‐negative BCP‐ALL cases. We selected SALL4 and ID2 as potential Z‐fusion‐specific transcriptional targets that might lead to the differentiation disorder of Z‐fusion‐positive ALL. The introduction of EP300‐ZNF384 and SYNRG‐ZNF384 induced the expression of these genes. Z‐fusion proteins exhibited stronger transcriptional activities on the promoter or enhancer region of these genes than Wild‐Z. Furthermore, GST pull‐down assay revealed that Z‐fusion proteins associated more strongly with EP300 than Wild‐Z. Coexpression of EP300 specifically enhanced the transcriptional activities of Z‐fusion proteins. We propose the increased EP300 binding of Z‐fusion proteins as a mechanism for their increased transcriptional activities. [ABSTRACT FROM AUTHOR]

Adult neuroblastoma is an extremely infrequent neoplasm, usually occurring in the adrenal medulla or in the paraspinal sympathetic ganglia, as its childhood counterpart. We report a very unusual case of a Schwannian stroma-poor adult neuroblastoma of inguinal location, showing aberrant expression of germ cell markers: SALL4 and OCT4. This aberrant marker expression, the unusual positivity for NKX2.2 and the very scattered (instead of diffuse strong) PHOX2B expression, complicated the initial diagnosis. In this case, the posttreatment histological evaluation revealed the neuroblastic nature of the lesion. Neuroblastoma maturation after treatment is an unusual finding in adults, and in this case, added an important clue for the final diagnosis. Germs cells markers expression in neuroblastoma is an interesting feature to explore and may define a subset of neuroblastomas with a different biological nature. [ABSTRACT FROM AUTHOR]

Bi-potential neuromesodermal progenitors (NMPs) produce both neural and paraxial mesodermal progenitors in the trunk and tail during vertebrate body elongation. We show that Sall4, a pluripotency-related transcription factor gene, has multiple roles in regulating NMPs and their descendants in post-gastrulation mouse embryos. Sall4 deletion using TCre caused body/tail truncation, reminiscent of early depletion of NMPs, suggesting a role of Sall4 in NMP maintenance. This phenotype became significant at the time of the trunk-to-tail transition, suggesting that Sall4 maintenance of NMPs enables tail formation. Sall4 mutants exhibit expanded neural and reduced mesodermal tissues, indicating a role of Sall4 in NMP differentiation balance. Mechanistically, we show that Sall4 promotion of WNT/β-catenin signaling contributes to NMP maintenance and differentiation balance. RNA-Seq and SALL4 ChIP-Seq analyses support the notion that Sall4 regulates both mesodermal and neural development. Furthermore, in the mesodermal compartment, genes regulating presomitic mesoderm differentiation are downregulated in Sall4 mutants. In the neural compartment, we show that differentiation of NMPs towards post-mitotic neuron is accelerated in Sall4 mutants. Our results collectively provide evidence supporting the role of Sall4 in regulating NMPs and their descendants. [ABSTRACT FROM AUTHOR]

Radiotherapy is the mainstay and primary curative treatment modality in nasopharyngeal carcinoma (NPC), whose efficacy is limited by the development of intrinsic and acquired radioresistance. Thus, deciphering new molecular targets and pathways is essential for enhancing the radiosensitivity of NPC. SALL4 is a vital factor in the development and prognosis of various cancers, but its role in radioresistance remains elusive. This study aimed to explore the association of SALL4 expression with radioresistance of NPC. It was revealed that SALL4 expression was closely correlated with advanced T classification of NPC patients. Inhibition of SALL4 reduced proliferation and sensitized cells to radiation both in vitro and in vivo. Furthermore, SALL4 silencing increased radiation‐induced DNA damage, apoptosis, and G2/M arrest in CNE2 and CNE2R cells. Moreover, knockdown of SALL4 impaired the expression of p‐ATM, p‐Chk2, p‐p53, and anti‐apoptosis protein Bcl‐2, while pro‐apoptosis protein was upregulated. These findings indicate that SALL4 could induce radioresistance via ATM/Chk2/p53 pathway and its downstream proteins related to apoptosis. Targeting SALL4 might be a promising approach for the development of novel radiosensitizing therapeutic agents for radioresistant NPC patients. [ABSTRACT FROM AUTHOR]

Thalidomide remains notorious as a result of the damage it caused to children born to mothers who used it to treat morning sickness between 1957 and 1961. The re-emergence of the drug to treat a range of conditions including erythema nodosum leprosum (a complication of leprosy) has led to a new generation of thalidomide damaged children being born in Brazil. Although thalidomide affects most of the developing tissues and organs of the body, the damage to the limbs is striking. Indeed phocomelia, the severe reduction or loss of the proximal long bones with retention of the distal hand/foot plate remains the stereotypical image of thalidomide. This review focuses on the type and range of damage thalidomide caused to the limbs, reviews current understanding of the mechanisms underlying thalidomide-induced limb malformations and outlines some of the challenges remaining in elucidating its teratogenicity. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence suggests that SALL4 plays oncogenic roles in cancer development and progression. We have previously shown that SALL4 is highly expressed in gastric cancer, and its upregulation is associated with lymph node metastasis and poor prognosis. The role of SALL4 in gastric cancer metastasis and the underlying mechanism remain unclear.Materials and methods: The biological roles of SALL4 in gastric cancer cell mobility, migration, and invasion were investigated by wound healing, transwell migration assay, and Matrigel invasion assay. The effects of SALL4 on epithelial–mesenchymal transition (EMT) in gastric cancer cells were examined by quantitative real-time PCR and Western blot. The downstream target genes of SALL4 were identified by microarray. The regulation of TGF-β1 by SALL4 in gastric cancer cells was analyzed by luciferase reporter assay and chromatin immunoprecipitation assay.Results: SALL4 knockdown inhibited, while SALL4 overexpression promoted the motility, migration, and invasion abilities of gastric cancer cells in vitro. SALL4 knockdown also suppressed the peritoneal metastasis of gastric cancer cells in nude mice. SALL4 knockdown suppressed, while SALL4 overexpression induced the activation of TGF-β/SMAD signaling pathway and triggered EMT in gastric cancer cells. TGF-β1 was identified as a direct target gene of SALL4. The results of chromatin immunoprecipitation study and luciferase reporter assay further confirmed that SALL4 bound to the promoter of TGF-β1 gene and activated its expression. TGF-β1 knockdown reversed SALL4-mediated promotion of gastric cancer cell motility, migration, and invasion, indicating that TGF-β1 acts as a downstream effector of SALL4. Furthermore, the expression of TGF-β1 was found to be closely associated with that of SALL4 in gastric cancer tissues.Conclusion: SALL4 promotes the metastasis of gastric cancer, at least partly, by directly activating TGF-β1, suggesting that SALL4 may serve as a new target for gastric cancer therapy. [ABSTRACT FROM AUTHOR]

There is increasing evidence that microRNAs (miRNAs) play important roles in tumor progression and development by targeting different genes, including gastric cancer (GC). However, the role of miR-16 in GC is so far unclear. Herein, we examined the function and potential mechanism of miR-16 in GC. Reverse transcription-quantitative PCR found that miR-16 expression was prominently lower in GC tissues while SALL4 expression was frequently higher than normal tissues. Re-expression of miR-16 could suppress GC cell proliferation and migration by MTT and Transwell assay. We confirmed that miR-16 directly targeted SALL4 in regulating GC by luciferase assay. Knockdown of SALL4 inhibited cell proliferation and migration. Furthermore, SALL4 could counteract the inhibition-effect of miR-16 in GC. In conclusion, for the the first time we demonstrated that miR-16 played inhibitory effect through targeting SALL4 in GC cell proliferation and migration. Our study revealed that miR-16/SALL4 axis was critical in regulating the GC development, indicating a new prospect to regulate GC cell progression and development. [ABSTRACT FROM AUTHOR]

Summary Cranial motor nuclei in the brainstem innervate diverse types of head and neck muscles. Failure in establishing these neuromuscular connections causes congenital cranial dysinnervation disorders (CCDDs) characterized by abnormal craniofacial movements. However, mechanisms that link cranial motor nuclei to target muscles are poorly understood at the molecular level. Here, we report that protocadherin-mediated repulsion mediates neuromuscular connection in the ocular motor system in zebrafish. We identify pools of abducens motor neurons that are topographically arranged according to soma size and convergently innervate a single muscle. Disruptions of Duane retraction syndrome-associated transcription factors reveal that these neurons require Mafba / MAFB, but not Sall4/SALL4, for differentiation. Furthermore, genetic perturbations of Pcdh17/protocadherin-17 result in defective axon growth and soma clumping, thereby abolishing neuromuscular connectivity. Our results suggest that protocadherin-mediated repulsion forms the central topography and efferent projection pattern of the abducens nucleus following Mafba-dependent specification and imply potential involvement of protocadherins in CCDD etiology. [ABSTRACT FROM AUTHOR]

Sal-like 4 (SALL4) is a nuclear factor central to the maintenance of stem cell pluripotency and is a key component in hepatocellular carcinoma, a malignancy with no effective treatment. In cancer cells, SALL4 associates with nucleosome remodeling deacetylase (NuRD) to silence tumor-suppressor genes, such as PTEN. Here, we determined the crystal structure of an amino-terminal peptide of SALL4(1-12) complexed to RBBp4, the chaperone subunit of NuRD, at 2.7 Å, and subsequent design of a potent therapeutic SALL4 peptide (FFW) capable of antagonizing the SALL4-NURD interaction using systematic truncation and amino acid substitution studies. FFW peptide disruption of the SALL4-NuRD complex resulted in unidirectional up-regulation of transcripts, turning SALL4 from a dual transcription repressor-activator mode to singular transcription activator mode. We demonstrate that FFW has a target affinity of 23 nM, and displays significant antitumor effects, inhibiting tumor growth by 85% in xenograft mouse models. Using transcriptome and survival analysis, we discovered that the peptide inhibits the transcription-repressor function of SALL4 and causes massive up-regulation of transcripts that are beneficial to patient survival. This study supports the SALL4-NuRD complex as a drug target and FFW as a viable drug candidate, showcasing an effective strategy to accurately target oncogenes previously considered undruggable. [ABSTRACT FROM AUTHOR]