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Background The long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 ( MALAT1 ) is a cancer biomarker. Furthermore, fusion of the MALAT1 gene with glioma-associated oncogene 1 ( GLI1 ) is a diagnostic marker of plexiform fibromyxoma and gastroblastoma; however, the function of this fusion gene remains unexplored. Method In this study, we elucidate the structure and function of the MALAT1::GLI1 fusion gene. To this end, we determined a transcriptional start site (TSS) and promoter region for truncated GLI1 expression using rapid amplification of the 5' cDNA end and a luciferase reporter assay in cultured cells transfected with a plasmid harboring the MALAT1::GLI1 fusion gene. Results We found that the TATA box, ETS1 motif, and TSS were located in MALAT1 and that MALAT1 exhibited transcriptional activity and induced expression of GLI1 from the MALAT1::GLI1 fusion gene. Truncated GLI1, lacking SUMOylation and SUFU binding sites and located in the nucleus, upregulated mRNA expression of GLI1 target genes in the hedgehog signaling pathway. Conclusions We demonstrate a distinct and alternative function of MALAT1 as a transcriptional promoter for expression of the MALAT1::GLI1 fusion gene. Our findings will aid future research on MALAT1 and its fusion gene partners.

We report 10 additional cases of GLI1-altered mesenchymal tumor to further delineate its clinicopathological and molecular spectrum. There were seven males and three females with a median age of 31 years (range 1.3 ~ 75 years). Five tumors arose in the oral cavity, one each in the stomach, uterine cervix, elbow, groin, and thigh. Histologically, all cases except one were composed of monomorphic round to epithelioid cells showing an infiltrative multinodular growth pattern. The neoplastic cells were surrounded by a rich network of capillary vessels. Vessel invasion or subendothelial protrusion into the vascular space was commonly present. One tumor developed regional lymph node metastasis. The remaining case showed a predominantly spindle cell tumor. By immunohistochemistry, most tumors showed diffuse staining of CD56 (8/8) with variable expression of S100 protein (7/8). In three tumors harboring amplified genes, strong and diffuse nuclear staining of MDM2 (2/3) and CDK4 (3/3) were noted. Next-generation sequencing (NGS) studies revealed GLI1 fusions in 7 cases and GLI1 amplification in 2 cases, which were validated by fluorescence in situ hybridization (FISH) analysis in the majority of cases. One case did not show fusion gene by RNA-seq, but FISH revealed both amplification and break-apart of GLI1 gene. Follow-up information showed local recurrences in two patients. All other patients remained disease-free at the last follow-up. Our study further demonstrates that mesenchymal tumors with GLI1 alterations represent a distinctive clinicopathological entity. Although the tumor has a propensity for the tongue, it can also arise in somatic soft tissues as well as in visceral organs. Based on the characteristic morphological features and genomic profiles, we propose the term “GLI1-altered mesenchymal tumor” to describe this emerging entity.

Mesenchymal neoplasms with GLI1 alterations have recently been reported in several anatomic locations. Their morphology and immunohistochemistry (IHC) are nonspecific, making their recognition a true challenge. To assess the diagnostic value of GLI1 and p16 IHC for identifying GLI1-altered neoplasms, we evaluated 12 such neoplasms (6 GLI1-amplified and 6 with GLI1-fusions) using the GLI1 IHC. Additionally, we evaluated some of their morphological and molecular mimickers, including glomangiomas, Ewing sarcomas (ES), myxoid liposarcomas, and MDM2/CDK4-amplified sarcomas (well-differentiated liposarcoma/WDLPS, dedifferentiated liposarcoma/DDLPS, and intimal sarcoma). All successfully tested GLI1-altered tumors (11/11) demonstrated at least moderate/strong nuclear and/or cytoplasmic GLI1 IHC positivity. GLI1-amplified tumors exhibited a moderate/strong predominantly nuclear staining, compared to a moderate, patchy, and predominantly cytoplasmic GLI1 positivity in GLI1-fusion tumors. Among their mimics, GLI1 immunoreactivity, either cytoplasmic or nuclear, was observed in intimal sarcoma (3/3) and WDLPS/DDLPS (22/25). GLI1 IHC demonstrated 92% sensitivity and 90.8% specificity in diagnosing GLI1-altered neoplasms. Strong/moderate nuclear/cytoplasmic p16 immunoexpression was noted in all GLI1-amplified tumors compared to none of fused cases. Overall, the GLI1/p16 combination demonstrated a sensitivity and specificity of 100% and 93% for GLI1-amplified tumors. In conclusion, we confirm that GLI1 IHC represents a good, quick, and cheap helpful screening tool. The inclusion of p16 may aid in pre-screening for potential GLI1-amplified neoplasms and provide insights on which tumors warrant further molecular testing.

Background: Several evidences suggest a marked angiogenic dependency in triple-negative breast cancer (TNBC) tumorigenesis and a potential sensitivity to anti-angiogenic agents. Herein, the putative role of Hedgehog (Hh) pathway in regulating TNBC-dependent angiogenesis was investigated. Methods: Expression and regulation of the Hh pathway transcription factor glioma-associated oncogene homolog1 protein (GLI1) were studied on the endothelial compartment and on TNBC-initiated angiogenesis. To evaluate the translational relevance of our findings, the combination of paclitaxel with the Smo inhibitor NVP-LDE225 was tested in TNBC xenografted mice. Results: Tissue microarray analysis on 200 TNBC patients showed GLI1 overexpression paired with vascular endothelial growth factor receptor 2 (VEGFR2) expression. In vitro , Hh pathway promotes TNBC progression in an autocrine manner, regulating the VEGF/VEGFR2 loop on cancer cell surface, and in a paracrine manner, orchestrating tumour vascularisation. These effects were counteracted by Smo pharmacological inhibition. In TNBC xenografted mice, scheduling NVP-LDE225 rather than bevacizumab provided a better sustained inhibition of TNBC cells proliferation and endothelial cells organisation. Conclusions: This study identifies the Hh pathway as one of the main regulators of tumour angiogenesis in TNBC, thus suggesting Hh inhibition as a potential new anti-angiogenic therapeutic option to be clinically investigated in GLI1 overexpressing TNBC patients.

Calcific aortic valve disease (CAVD) is the most prevalent human valve disease worldwide. Multiple factors induce \"irreversible\" pathological changes in the aortic valve leaflets, resulting in changes in cardiac hemodynamics, eventually leading to heart failure. However, no effective pharmaceutical interventions have been found and prosthetic valve replacement is the only curative approach. Glioma-associated oncogene 1 (Gli1) exerts a regulatory role on cardiovascular diseases, and it is already a therapeutic target to combat tumors. Our research aimed to explore the role and basic mechanism of Gli1 in CAVD, to pave the way for the discovery of effective drugs in the treatment of CAVD. Human aortic valve tissues were obtained to evaluate Gli1 expression and primary valve interstitial cells (VICs) were used to perform related experiments. The results showed that Gli1 promoted cell proliferation and significantly accelerated cell osteogenic transformation through the up-regulation of the osteogenic factors Runx2 and Alp, in turn through the AKT signaling pathway by targeting P130cas expression. Furthermore, Gli1 was activated by TGF-β and sonic hedgehog through the canonical and non-canonical Hedgehog signaling pathways in VICs. Our results indicated that Gli1 promoted cell proliferation and accelerated cell osteogenic transformation in VICs, providing a new strategy for the therapy of CAVD by targeting Gli1.

Sonic hedgehog (Shh) is a secreted protein with important roles in mammalian embryogenesis. During tooth development, Shh is primarily expressed in the dental epithelium, from initiation to the root formation stages. A number of studies have analyzed the function of Shh signaling at different stages of tooth development and have revealed that Shh signaling regulates the formation of various tooth components, including enamel, dentin, cementum, and other soft tissues. In addition, dental mesenchymal cells positive for Gli1, a downstream transcription factor of Shh signaling, have been found to have stem cell properties, including multipotency and the ability to self-renew. Indeed, Gli1-positive cells in mature teeth appear to contribute to the regeneration of dental pulp and periodontal tissues. In this review, we provide an overview of recent advances related to the role of Shh signaling in tooth development, as well as the contribution of this pathway to tooth homeostasis and regeneration.

Aberrant epithelial reprogramming can induce metaplastic differentiation at sites of tissue injury that culminates in transformed barriers composed of scar and metaplastic epithelium. While the plasticity of epithelial stem cells is well characterized, the identity and role of the niche has not been delineated in metaplasia. Here, we show that Gli1+ mesenchymal stromal cells (MSCs), previously shown to contribute to myofibroblasts during scarring, promote metaplastic differentiation of airway progenitors into KRT5+ basal cells. During fibrotic repair, Gli1+ MSCs integrate hedgehog activation signalling to upregulate BMP antagonism in the progenitor niche that promotes metaplasia. Restoring the balance towards BMP activation attenuated metaplastic KRT5+ differentiation while promoting adaptive alveolar differentiation into SFTPC+ epithelium. Finally, fibrotic human lungs demonstrate altered BMP activation in the metaplastic epithelium. These findings show that Gli1+ MSCs integrate hedgehog signalling as a rheostat to control BMP activation in the progenitor niche to determine regenerative outcome in fibrosis.Cassandras et al. show that Gli1-expressing mesenchymal stromal cells promote metaplastic differentiation of airway progenitors into basal cells by antagonizing BMP signalling in lung fibrosis.

Background Gli1 has been identified as a marker of osteogenic progenitors in the condylar subchondral bone. The Wnt/β-catenin signaling pathway is known to regulate stem cell proliferation and differentiation in bone. Whether Wnt/β-catenin signaling pathway could influence Gli1 + osteogenic progenitors remains unclear. Here, we aimed to investigate the role and related mechanisms of Wnt/β-catenin signaling in the regulation of Gli1 + osteogenic progenitors in condylar development and temporomandibular joint osteoarthritis (TMJOA). Methods We generated Gli1-Cre ERT2 ; tdTomato mice to perform lineage tracing; We generated Gli1-Cre ERT2 ; β-catenin fl/fl mice, in which β-catenin was lost in the Gli1 + lineage to examine the role of Wnt/β-catenin signaling pathway in regulating the proliferation and differentiation of Gli1 + cells. The β-catenin CKO mice and their wild-type (WT) littermates were induced at 3 days and were euthanized 1, 2 or 4 weeks after induction; We induced a TMJOA model through a unilateral partial discectomy (UPD) of the temporomandibular joint disc in 6-week-old tamoxifen-treated Gli1-Cre ERT2 ; β-catenin fl/fl ; tdTomato mice and control group ( Gli1-Cre ERT2 ; tdTomato mice). We harvested the mandibles at 4 weeks post-surgery. Results Conditional knockout of β-catenin inhibited the osteogenic activity of Gli1 + progenitor cells during condylar subchondral bone development. In discectomy-induced TMJOA, the overactivation of Gli1 in subchondral bone drove pathological osteogenesis and aberrant subchondral bone remodeling. Deletion of β-catenin in Gli1 + cells mitigated excessive Gli1 + cells activation and ectopic mineralization. Conclusion Our findings establish Wnt/β-catenin signaling as a key regulator of Gli1 + progenitor cell fate determination in both bone development and TMJOA pathogenesis.

The hedgehog signaling pathway is a vital factor for embryonic development and stem cell maintenance. Dysregulation of its function results in tumor initiation and progression. The aim of this research was to establish a disease model of hedgehog-related tumorigenesis with Gorlin syndrome-derived induced pluripotent stem cells (GS-iPSCs). Induced neural progenitor cells from GS-iPSCs (GS-NPCs) show constitutive high GLI1 expression and higher sensitivity to smoothened (SMO) inhibition compared with wild-type induced neural progenitor cells (WT-NPCs). The differentiation process from iPSCs to NPCs may have similarity in gene expression to Hedgehog signal-related carcinogenesis. Therefore, GS-NPCs may be useful for screening compounds to find effective drugs to control Hedgehog signaling activity.

As a transcription factor, GLI1 plays an important role in cell cycle regulation, DNA replication, and DNA damage responses. The aberrant activation of GLI1 has been associated with cancers such as glioma, osteosarcoma, and rhabdomyosarcoma. The binding of GLI1 to a specific DNA sequence was achieved by five tandem zinc finger motifs (Zif motifs) on the N-terminal part of the molecule. Here, we reported a novel homodimeric crystal structure of Zif1-2. These two Zif motifs are linearized. Namely, Zif2 does not bend and interact with Zif1 of the same molecule. Instead, Zif1 from one molecule interacts with Zif2 from another molecule. The dimer interface of Zif1-2 is unique and different from the conformation of Zif1-2 from the GLI1-DNA co-crystal structure. The dimeric conformation of Zif motifs could represent the native conformation of apo form GLI1 Zif motifs in the cell. The molecular dynamics simulation result of the homodimer, the in silico mutagenesis, and the predicted protease stability of these mutants using a large language model are also presented.