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Targeting Subgroup-specific Cancer Epitopes for Effective Treatment of Pediatric Medulloblastoma
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Sidharth Mahapatra, Naveenkumar Perumall
During embryonic growth, neural precursor cells generated in the rhombic lip of the dorsal hindbrain migrate along the surface of the cerebellum to form the external granule layer (EGL). The secretion of bone morphogenic proteins (BMPs), such as BMP6, BMP7, and GDF7, encourages further proliferation generating a rich pool of granule cell precursors (GCPs) in the developing EGL [20, 36]. As older cells exit the EGL and migrate through a layer of Purkinje cells, they encounter the Hedgehog pathway ligand, Sonic hedgehog (SHH), a highly conserved embryonic signaling system which binds to its receptor, Patched 1 (PTCH1), expressed on GCPs in the EGL [37, 38]. Downstream effectors include the GLI family of transcription factors (GLI1, GLI2, and GLI3), which activate transcription of genes, such as cyclinD1 (CCND1) and MYC, thereby facilitating GCP proliferation and migration [7, 20, 36, 39]. After post-natal cerebellar development, this pathway goes dormant with the 12-pass transmembrane receptor, PTCH1, keeping the 7-pass transmembrane protein, Smoothened (SMO), in an inactivated state [40]. This, in turn, leads to the sequestration of downstream effectors of the SHH pathway by Suppressor-of-Fused (SUFU), effectively silencing gene expression [7]. Deregulated binding of SHH to PTCH1 releases and constitutively activates SMO which, in turn, inhibits SUFU, leading to release and nuclear translocation of GLI1-3; as a result, aberrant gene transcription is activated, facilitating phenotypic transformation into medulloblastoma [7].
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
TAK-441 (Figure 6.71) is a potent and selective experimental SMO antagonist that blocks Hh signaling. It has been shown to inhibit expression of human Gli1 messenger mRNA with an EC50 of 1.9 nM in MRC5 human embryonic fibroblasts, and is thought to work by binding to SMO. Structure of the experimental Hedgehog pathway inhibitor TAK-441.
Soft Tissue Sarcomas
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Thomas F. DeLaney, David C. Harmon, Karol Sikora, Francis J. Hornicek
Other chromosomal changes characteristic of specific sarcoma type include the reciprocal exchange t(11:22)(q24;ql2) seen in approximately 85%–90% of Ewing’s sarcoma and primitive peripheral neuro-ectodermal tumor (PNET). In this translocation, the EWS (Ewing sarcoma breakpoint region 1) gene from chromosome 22q12 is covalently linked to the erythroblast transformation-specific (ETS) family member, FLI-1, to form the EWS–FLI-1 fusion gene.15 The chimeric proteins that result from this translocation may alter transcription of a number of genes including upregulation of the transcription factor Gli1 that promotes the oncogenic potential of the Hedgehog pathway. A less common translocation t(21;22)(q22;q12) has also been identified and links EWS to a different ETS family member, ETS-related gene (ERG). Myxoid and round cell subtypes of liposarcomas display a reciprocal translocation t(12;16) (q13;p11). In this translocation, the CHOP (induced by DNA damage) gene is inserted adjacent to a novel gene called TLS. The fusion gene, called TLS–CHOP, shows sequence homology to the Ewing’s fusion gene. It fails to induce G1/S arrest, which is one of the functions of the non-oncogenic form of CHOP (GADD153). Identification of the fusion gene has been used as a diagnostic aid for these subtypes of liposarcoma.
Patched 1 and C-C Motif Chemokine Receptor 6 Distinguish Heterogeneous T Helper 17 Subsets in Colitic Lamina Propria
Published in Immunological Investigations, 2023
Shengli Pei, Chao Ke, Jiantao Han, Xingwang Xie
The present study first unveiled the expression of important Hedgehog signaling components in Th17 cells in colitis development. The frequency of Th17 cells was boosted in both mLN and LP CD4+ T lymphocytes after colitis induction, indicating that Th17 response was initiated and promoted during the development of colitis. The transcripts of PTCH1, SMO, and Gli1 were not significantly altered in mLN Th17 cells after the onset of colitis, suggesting that the differentiation and activation of Th17 cells do not influence the transcription of these molecules. In contrast, the changes in PTCH1, SMO, and Gli1 in LP Th17 cells suggest that LP-specific factors, perhaps inflammatory mediators, enhance the transcription of these molecules. Interestingly, Gli3 was increased in both mLN Th17 cells and LP Th17 cells after the onset of colitis, signifying the activation of the hedgehog signaling in colitis-responsive Th17 cells. Therefore, our study might support the conclusion of the latest study showing that the Hedgehog signaling particularly Gli3 controls Th17 differentiation (Hanna et al. 2022). Because Gli1 itself is the target gene of the Hedgehog signaling (Carballo et al. 2018), the remarkable increase in Gli1 implies the activation of the Hedgehog signaling in LP Th17 cells.
Acupuncture combined with moxibustion promote the recovery of spinal cord injury in correlation with Shh/Gli-1 signaling pathway
Published in The Journal of Spinal Cord Medicine, 2022
Li-Li-Qiang Ding, Song-Feng Hu, Xing-Wei He, Peng Zhang, Fen-Fen Zhao, Ting-Ping Liu, Qin Zhang, Fan He, Ying Yu, Peng Xiong, Chang-Kang Wang
The Hh pathway has been shown to be activated in nerve damage, and may serve as a potential approach for treating neurodegenerative diseases and dysfunction such as SCI.13 In terms of nerve injury and regeneration, the Shh signaling pathway has a protective role in pathological injury after SCI.14 Studies showed that SCI caused the differentiation of nearby progenitors to scar-producing astrocytes 15 inhibiting the elongation and myelination of axons, finally prevented the re-establish the neural circuitry required for regeneration.16 However the expression of Shh reduced that progress after SCI, those researchers considered Shh signaling pathway as a potential therapy for enhancing regeneration following spinal cord injury.17 Shh is produced in reactive astrocytes after the cerebral cortex injury and participated in regulating the remyelination of injured axons after brain injury.18 Gli-1 is one of three homologs of cytoplasmic zinc finger protein. Shh releases the associated signaling transducer Smo, resulting in upregulation and nuclear translocation of Gli transcription factors.19 Gli is translocated to the nucleus leading to transcriptional activation of Hh target genes, including Gli itself and Patched (Ptc), and take part in the process of promoting regeneration of Hh pathway.
Long-Term Glucose Restriction with or without β-Hydroxybutyrate Enrichment Distinctively Alters Epithelial-Mesenchymal Transition-Related Signalings in Ovarian Cancer Cells
Published in Nutrition and Cancer, 2021
Hossein Ghahremani, Saeedeh Nabati, Hanieh Tahmori, Tahmineh Peirouvi, Majid Sirati-Sabet, Siamak Salami
Gli1 is the key EMT stimulating transcription factor of the Hedgehog pathway. Ke et al. showed that puromorphamine elicited invasiveness and metastasis in A2780 and SK-OV-3 cells increased expression of Gli1, stimulated the PI3K-AKT pathway, and fueled the EMT process (62). We also assessed the expressions of some key components of the Hedgehog pathway including SMO, SUFU, and GLI1 which revealed that glucose restriction and bHB enrichment was not significantly changed their expressions in A2780CP cells. These results are in agreement with the other study investigating the effect of a ketogenic diet on components of the Hedgehog pathway in a mouse model of medulloblastoma (63). On the contrary, GLI1 gene expression was significantly decreased in bHB-ENR and GLC-RES SK-OV-3 cells. Also, the expression of the SMO gene was significantly decreased by bHB-enrichment in glucose restricted SK-OV-3 cells.