Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hedgehog signaling is aberrantly activated in glioma, medulloblastoma, basal cell carcinoma, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, breast cancer, and other tumors. Hedgehog signals activate GLI family members via Smoothened. RTK signaling potentiates GLI activity through PI3K-AKT-mediated GSK3 inactivation or RAS-STIL1-mediated SUFU inactivation, while GPCR signaling to Gs represses GLI activity through adenylate cyclase-mediated PKA activation. GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin. Hedgehog signals are fine-tuned based on positive feedback loop via GLI1 and negative feedback loop via PTCH1, PTCH2, and HHIP1. Excessive positive feedback or collapsed negative feedback of Hedgehog signaling due to epigenetic or genetic alterations leads to carcinogenesis. Hedgehog signals induce cellular proliferation through upregulation of N-Myc, Cyclin D/E, and FOXM1. Hedgehog signals directly upregulate JAG2, indirectly upregulate mesenchymal BMP4 via FOXF1 or FOXL1, and also upregulate WNT2B and WNT5A. Hedgehog signals induce stem cell markers BMI1, LGR5, CD44 and CD133 based on cross-talk with WNT and/or other signals. Hedgehog signals upregulate BCL2 and CFLAR to promote cellular survival, SNAI1 (Snail), SNAI2 (Slug), ZEB1, ZEB2 (SIP1), TWIST2, and FOXC2 to promote epithelial-to-mesenchymal transition, and PTHLH (PTHrP) to promote osteolytic bone metastasis. KAAD-cyclopamine, Mu-SSKYQ-cyclopamine, IPI-269609, SANT1, SANT2, CUR61414 and HhAntag are small-molecule inhibitors targeted to Smoothened, GANT58, GANT61 to GLI1 and GLI2, and Robot-nikinin to SHH. Hedgehog signaling inhibitors should be used in combination with RTK inhibitors, GPCR modulators, and/or irradiation for cancer therapy.
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PMID:Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation. 1986 Jun 66

Gliomas are the most common primary tumors in adult central nervous system and result in disappointing survival outcomes. FOXL1, as a transcription factor, plays an important role in regulating the expression of genes involved in cell metabolism, proliferation and differentiation. In this study, we investigated the relationship between FOXL1 expression and prognosis of patients with glioma. We selected 611 glioma patients from The Cancer Genome Atlas (TCGA) database and 132 glioma patients from Huai'an First People's Hospital (PFHH). The prognostic values of FOXL1 in glioma were analyzed in both cohorts. In TCGA cohort, the median (10.2389) was used as the cut-off value of FOXL1 mRNA levels in tumor tissue. Kaplan-Meier analysis showed that higher WHO glioma grade (P<0.001) and expression of FOXL1 (P<0.001) were associated with worse overall survival (OS). The univariate Cox regression model revealed that age (P<0.001), WHO grade (P<0.001), histological type (P<0.001) and FOXL1 expression (P<0.001) were associated with prognosis of glioma patients. In PFHH cohort, expression of FOXL1 in tumor cells was detected by immunohistochemistry (IHC) staining based on a tissue microarray (TMA) sample. Kaplan-Meier analysis also showed that WHO glioma grade (P<0.001) and expression of FOXL1 (P=0.012) were associated with OS in glioma patients. The univariate Cox regression showed that WHO grade (P=0.001), histological type (P<0.001) and FOXL1 expression (P=0.013) were associated with prognosis of glioma patients. In both cohorts Kaplan-Meier subgroup analyses showed FOXL expression correlated with OS in high WHO grade subgroup, while low grade subgroup showed no such correlation. This study showed that higher expression of FOXL1 is associated with poor OS of glioma patients in TCGA and PFHH cohorts. Especially, FOXL1 overexpression is associated with worse outcomes in high WHO grade subgroup. Our findings suggest that FOXL1 expression is a candidate predictor of clinical outcome in glioma patients and may act as an effective molecular marker for immunotherapeutic strategies of glioma patients in clinical practice.
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PMID:FOXL1 overexpression is associated with poor outcome in patients with glioma. 3128 50