Explore the vast range of titles available.

AimsCutaneous syncytial myoepithelioma (CSM) is a rare myoepithelioma variant of skin, characterized by intradermal syncytial growth of spindle cells with a distinct immunophenotype of EMA and S100 positivity and infrequent keratin expression. While CSM was first described as a cutaneous tumor, singular non-cutaneous cases have since been reported in bone. We aimed to investigate the clinicopathological features of this variant across all anatomic sites through a large multi-institutional study.Methods and resultsWe complied a total of 24 myoepitheliomas with syncytial growth from our files. The tumors occurred in 12 male and 12 female patients (M:F = 1:1), with a median age of 31 years (range, 9–69 years). While the majority of tumors (75%, n = 18) occurred in skin, a significant subset (25%, n = 6) arose in non-cutaneous sites, including bone (n = 3), bronchus/trachea (n = 2), and interosseous membrane of tibia/fibula (n = 1). Tumor size ranged from 0.4 to 5.9 cm. Clinical follow-up (7 patients; range 14–202 months; median 56.5 months) showed a single local recurrence 8 years after incomplete skin excision but no metastases; all patients were alive at the time of last follow-up without evidence of disease. Histologically, all tumors were pink at low-power and characterized by a syncytial growth of bland ovoid, spindled, or histiocytoid cells with eosinophilic cytoplasm and prominent perivascular lymphoplasmacytic inflammation. One-third displayed adipocytic metaplasia (8/24). Rare cytologic atypia was seen but was not associated with increased mitotic activity. All tumors expressed S100, SMA, and/or EMA. Keratin expression was absent in most cases. Molecular analysis was performed in 16 cases, all showing EWSR1-rearrangments. In total, 15/15 (100%) harbored an EWSR1::PBX3 fusion, whereas 1 case EWSR1 FISH was the only molecular study performed.ConclusionSyncytial myoepithelioma is a rare but recognizable morphologic variant of myoepithelioma which may have a predilection for skin but also occurs in diverse non-cutaneous sites. Our series provides evidence supporting a reappraisal of the term “cutaneous syncytial myoepithelioma,” as 25% of patients in our series presented with non-cutaneous tumors; thus, we propose the term “syncytial myoepithelioma” to aid pathologist recognition and avoidance of potentially confusing terminology when referring to non-cutaneous examples. The behavior of syncytial myoepithelioma, whether it arises in cutaneous or non-cutaneous sites, is indolent and perhaps benign with a small capacity for local recurrence.

Background Laryngeal squamous cell carcinoma (LSCC) is a common malignant tumor of the head and neck. LSCC patients have seriously impaired vocal, respiratory, and swallowing functions with poor prognosis. Circular RNA (circRNA) has attracted great attention in cancer research. However, the expression patterns and roles of circRNAs in LSCC remain largely unknown. Methods RNA sequencing was performed on 57 pairs of LSCC and matched adjacent normal mucosa tissues to construct circRNA, miRNA, and mRNA expression profiles. RT-PCR, qPCR, Sanger sequencing, and FISH were undertaken to study the expression, localization, and clinical significance of circCORO1C in LSCC tissues and cells. The functions of circCORO1C in LSCC were investigated by RNAi-mediated knockdown, proliferation analysis, EdU staining, colony formation assay, Transwell assay, and apoptosis analysis. The regulatory mechanisms among circCORO1C , let-7c-5p , and PBX3 were investigated by luciferase assay, RNA immunoprecipitation, western blotting, and immunohistochemistry. Results circCORO1C was highly expressed in LSCC tissues and cells, and this high expression was closely associated with the malignant progression and poor prognosis of LSCC. Knockdown of circCORO1C inhibited the proliferation, migration, invasion, and in vivo tumorigenesis of LSCC cells. Mechanistic studies revealed that circCORO1C competitively bound to let-7c-5p and prevented it from decreasing the level of PBX3 , which promoted the epithelial–mesenchymal transition and finally facilitated the malignant progression of LSCC. Conclusions circCORO1C has an oncogenic role in LSCC progression and may serve as a novel target for LSCC therapy. circCORO1C expression has the potential to serve as a novel diagnostic and prognostic biomarker for LSCC detection.

BackgroundThe importance of long noncoding RNAs (lncRNAs) has been identified in human cancers, such as emerged as tumor facilitator or tumor suppressor. Small nucleolar RNA host gene 10 (SNHG10) has been reported as an oncogenic lncRNA in hepatocellular carcinoma. However, its functional role and underlying mechanism in gastric cancer (GC) need to be further explored.AimsOur study was conducted to investigate the function and molecular mechanism of SNHG10 in GC.MethodsSNHG10 expression was detected by qRT-PCR. The effect of SNHG10 on GC cell growth was assessed by colony formation, EdU, JC-1, flow cytometry, and wound-healing assays. The interaction between SNHG10 and PBX3 was confirmed through ChIP and luciferase reporter assay. RIP and RNA pull down assays was used to define the binding of DEAD-box helicase 54 (DDX54) to SNHG10 or PBX homeobox 3 (PBX3).ResultsSNHG10 was expressed at a high level in GC cells. SNHG10 knockdown resulted in the inhibition on GC cell proliferation, migration but induced cell apoptosis. PBX3 could interact with SNHG10 promoter and thereby activate the expression of SNHG10. Subsequently, it was confirmed that SNHG10 positively modulated the expression of PBX3. Based on this, we found that DDX54 could bind to SNHG10 and PBX3, suggesting that SNHG10 maintained PBX3 mRNA stability through recruiting DDX54. Restoration assays indicated that PBX3 overexpression recovered SNHG10 silencing-induced inhibition on GC cell growth.ConclusionsSNHG10 facilitates cell growth by affecting DDX54-mediated PBX3 mRNA stability in GC.

Background Circular RNAs (circRNAs) function as crucial regulators in multiple cancers, including hepatocellular carcinoma (HCC). However, the roles of circRNAs in HCC remains largely unknown. Methods circTOLLIP was identified in HCC by screening of two public circRNA microarray datasets and detected in HCC cells and tissues through quantitative real-time PCR (qRT–PCR) and in situ hybridization (ISH). Gain- and loss-of-function assays were performed to confirm the biological effects of circTOLLIP on HCC in vitro and in vivo. Mechanistically, bioinformatics analysis of online databases, MS2-RNA pulldown, biotin-labeled circTOLLIP/miR-516a-5p RNA pulldown, RNA immunoprecipitation (RIP), luciferase reporter assay, fluorescence in situ hybridization assay (FISH) and RNA sequencing were used to confirm the regulation of Eukaryotic initiation factor 4A3 (EIF4A3) on circTOLLIP and the interaction among circTOLLIP, miR-516a-5p and PBX homeobox 3 (PBX3). Results circTOLLIP was significantly upregulated in HCC cells and tissues. High circTOLLIP expression was correlated with poor overall survival (OS) and disease-free survival (DFS) in patients. circTOLLIP promoted the proliferation and metastasis of HCC cells in vitro and in vivo. Mechanistically, EIF4A3 promoted the biogenesis of circTOLLIP without affecting its stability. Moreover, circTOLLIP sponged miR-516a-5p to elevate the expression of PBX3, thereby activating the epithelial-to-mesenchymal transition (EMT) pathway and facilitating tumor progression in HCC. Conclusions Our findings indicate that EIF4A3-induced circTOLLIP promotes the progression of HCC through the circTOLLIP/miR-516a-5p/PBX3/EMT axis.

PBX3 is a homeodomain-containing transcription factor of the pre-B cell leukemia (PBX) family, members of which have extensive roles in early development and some adult processes. A number of features distinguish PBX3 from other PBX proteins, including the ability to form specific and stable interactions with DNA in the absence of cofactors. PBX3 has frequently been reported as having a role in the development and maintenance of a malignant phenotype, and high levels of PBX3 tumor expression have been linked to shorter overall survival in cancer. In this review we consider the similarities and differences in the function of PBX3 in different cancer types and draw together the core signaling pathways involved to help provide a better insight into its potential as a therapeutic target.

ObjectiveMyocardial infarction (MI) is a major cause of cardiovascular disease which poses great healthy and financial burden for individuals. MI can be mainly induced by hypoxia. Therefore, in this study, we aimed to explore the function and mechanism of lncRNA H19 on hypoxia-induced pyroptosis of cardiomyocytes.MethodPeripheral blood from healthy controls and MI patients was collected for determination of mRNA and protein expression levels of H19 and CYP1B1. The correlation between these two factors was analyzed. Then MI rat model was established and injected with H19 overexpression/CYP1B1 knockdown plasmid, in which the infraction area and pathological morphology were observed. Hypoxic cardiomyocytes were transfected with overexpression or knockdown of H19 and CYP1B1 for determination of NLRP3, ASC, caspase-1, IL-1β, IL-18, CyclinD1, and PCNA. Cell proliferation ability was assessed by CCK8. RIP and dual luciferase gene reporter assay were applied to verify the binding among H19, PBX3 and CYP1B1.ResultsDownregulated H19 and upregulated CYP1B1 were observed in MI patients. A negative correlation was found for H19 and CYP1B1 expressions. Transfection of H19 overexpression or CYP1B1 knockdown could attenuate the MI progression in MI rats. In hypoxic cardiomyocytes, H19 overexpression or CYP1B1 knockdown could also inhibit NLRP3, ASC, caspase-1, IL-1β, and IL-18 in addition to suppressing cell apoptosis rate and promoting cell proliferation rate. Different expression pattern was found in cells transfected with H19 knockdown or CYP1B1 overexpression. Overexpression of CYP1B1 could abrogate the suppressive effect of H19 on pyroptosis of cardiomyocytes. H19 could inhibit activity of CYP1B1 promoters by regulating PBX3.ConclusionH19 could inhibit CYP1B1 expression in a PBX3-dependent way and thus attenuate cell pyroptosis of cardiomyocytes.

Soft tissue myoepithelial tumors (METs) are diagnostically challenging tumors that require careful histologic and immunohistochemical characterization for accurate classification. Nearly half of METs show recurrent EWSR1 or FUS gene rearrangements with a diverse set of fusion partners. The diversity of fusion partners and lack of known driver abnormalities in many cases raises the question of whether METs represent a uniformly distinct tumor entity. To address this question, we performed careful histopathologic and molecular analysis, including DNA methylation profiling (DNA-MP) and fusion testing, on a cohort of 30 institutionally diagnosed METs from 29 patients. On histologic and immunophenotypic evaluation, 22 of 30 tumors diagnosed as MET fulfilled strict histologic and immunophenotypic criteria. Among those failing to meet criteria, most were reclassified as another tumor entity by DNA-MP. Seven tumors meeting criteria grouped with another sarcoma reference type by DNA-MP, with confirmation of the characteristic driver abnormality of that tumor in selected cases. The remaining tumors histologically “consistent” with METs ( n  = 15) formed a distinct epigenetic cluster, independent of other reference entities. Recurrent gene fusions were identified in 11 of 15 tumors in this epigenetically distinct group, including EWSR1 :: KLF15 ( n  = 4), EWSR1 :: PBX3 ( n  = 2), and EWSR1 :: POU5F1 ( n  = 1) rearrangements. Clinicopathologic correlation suggests that EWSR1 :: KLF15 tumors are enriched in pediatric patients with aggressive histology. Our work shows that at least a subset of METs falls within an epigenetically distinct but heterogenous group. Furthermore, DNA-MP provides a useful adjunct to other molecular testing to help distinguish METs from histologic mimics.

Metabolic reprogramming is a hallmark of cancers crucial for fulfilling the needs of energy, building blocks, and antioxidants to support tumor cells' rapid proliferation and to cope with the harsh microenvironment. Pre-B-cell leukemia transcription factor 3 (PBX3) is a member of the PBX family whose expression is up-regulated in various tumors, however, whether it is involved in tumor cell metabolic reprogramming remains unclear. Herein, we report that PBX3 is a positive regulator of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway (PPP). PBX3 promoted G6PD transcriptional activity in tumor cells by binding directly to its promoter, leading to PPP stimulation and enhancing the production of nucleotides and NADPH, a crucial reductant, thereby promoting nucleic acid and lipid biosynthesis while decreasing intracellular reactive oxygen species levels. The PBX3/G6PD axis also promoted tumorigenic potential in vitro and in vivo. Collectively, these findings reveal a novel function of PBX3 as a regulator of G6PD, linking its oncogenic activity with tumor cell metabolic reprogramming, especially PPP. Furthermore, our results suggested that PBX3 is a potential target for metabolic-based anti-tumor therapeutic strategies.

Tumor cells alter lipid metabolic pathways to meet their demands for energy and membrane biosynthesis. Despite its crucial role in tumor cell growth, survival, and metastasis, the mechanisms underlying tumor cell lipid metabolic reprogramming remain poorly understood. Pre-B-cell leukemia transcription factor 3 (PBX3), a member of the PBX family, could promote tumorigenesis; however, whether it is involved in tumor lipid metabolic reprogramming remains unknown. Herein, we found that PBX3 significantly promotes tumor growth by enhancing lipid accumulation in HCC cells. By assessing the effect of PBX3 on the expression levels of lipid metabolism-related genes, we found that PBX3 could positively regulate the expression of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR), a rate-limiting enzyme in the cholesterol biosynthesis pathway. Mechanistically, we revealed that PBX3 could directly bind to the −167/−151 region of HMGCR promoter, thereby increasing its transcriptional activity and, subsequently, its expression level. This leads to the increase of HCC cell cholesterol biosynthesis and, eventually, to the increase of the in vivo tumorigenic potential. Collectively, our research revealed an unprecedented regulatory mechanism of cholesterol metabolism in HCC cells through PBX3 positive regulation on HMGCR expression levels. These findings provide novel insights into tumor metabolic reprogramming and uncover a previously unknown physiological function for PBX3. Moreover, these results suggest the potential of targeting PBX3 as an anti-tumor therapeutic strategy.

The abnormal expression of PHAX was observed in esophageal cancer, however, its specific function and mechanism remain to be further elucidated. We demonstrated that PHAX, LIN28B, and PBX3 were upregulated in esophageal cancer, while TET2 was downregulated. Elevated PHAX correlated with adverse outcomes among esophageal cancer patients. PHAX or PBX3 knockdown not only inhibited esophageal cancer cell proliferation, and promoted apoptosis and autophagy in vitro, but it also repressed tumor growth and lung metastasis in mice. Mechanically, PHAX stabilized PBX3 mRNA through interacting with LIN28B. PBX3 directly bound to the TET2 promoter region and inhibited its expression. In conclusion, PHAX directly bound to LIN28B and enhanced LIN28B‐mediated stabilization of PBX3 mRNA, leading to upregulation of PBX3. PBX3 then transcriptionally repressed TET2 expression to promote esophageal cancer cell proliferation, and suppress apoptosis and autophagy. Targeting this signaling cascade could represent a promising therapeutic strategy for esophageal cancer. PHAX was upregulated in esophageal cancer and promoted cancer cell proliferation, while inhibiting apoptosis and autophagy. PHAX contributed to tumor growth and lung metastasis through suppressing autophagy in vivo. PHAX enhanced LIN28B‐mediated PBX3 mRNA stability by directly binding to LIN28B. PHAX promoted esophageal cancer cell proliferation and repressed apoptosis and autophagy by regulating the LIN28B/PBX3 axis. PBX3 facilitated esophageal cancer cell proliferation and inhibited apoptosis and autophagy through binding to the TET2 promoter region.