BACKGROUNDMedulloblastoma is a pediatric malignant brain tumor associated with an aberrantly activated Shh pathway. The Shh pathway acts via downstream effector molecules, including Pax6 and Nkx2.2. Transcription factor Nkx2.2 plays crucial roles during early embryonic patterning and development. In this study, we aimed to determine the role of transcription factor Nkx2.2 in medulloblastoma development.METHODS AND RESULTSHere, whole transcriptome levels and suppressive effect of transcription factor Nkx2.2 on Pax6 were assessed using one normal human brain and three surgically removed medulloblastoma samples. Additionally, protein levels of Shh, Gli1, Pax6, and Nkx2.2 and co-expression patterns of Pax6 and Nkx2.2 were assessed in 14 medulloblastoma samples. Quantitative reverse transcription-polymerase chain reaction revealed the suppressive effect of Nkx2.2 on Pax6. D283 cells were treated with the Shh pathway activator, SAG, and Gli1 inhibitor, GANT61, which revealed Pax6-Nkx2.2 regulation. Increased cell proliferation was observed in D283 cells transfected with Nkx2.2 small interfering RNA. Moreover, mRNA expression levels of Shh, Pax6, Nkx2.2, and Gli1 were assessed in Daoy cells transfected with Gli1 and Nkx2.2 small interfering RNAs using quantitative reverse transcription-polymerase chain reaction. Pax6 levels were increased in Nkx2.2 siRNA-transfected cells.CONCLUSIONSAberrantly activated Shh pathway leads to the ectopic expression of Pax6 in granular cells, inducing medulloblastoma development. Moreover, Nkx2.2 transcription factor acts as a suppressor of Pax6 during medulloblastoma development and maintenance. Overall, this study provides novel insights for the development of effective therapeutic strategies and suggests potential targets for medulloblastoma.

01 Sep 2024·Hematological Oncology

Combined targeting of Hedgehog/GLI1 and Wnt/β‐catenin pathways in mantle cell lymphoma

Article

Author: Han, Yan ; Gao, Jingjing ; Chen, Qi ; Chen, Hongyuan ; Liu, Shengquan ; Xiao, Huifang ; He, Yanjun ; Zhu, Xiongpeng ; Li, Chuntuan ; Zheng, Yan

AbstractMantle cell lymphoma (MCL) is a rare and aggressive form of non‐Hodgkin lymphoma. Challenges in its treatment include relapse, drug resistance, and a short survival period. The Hedgehog/GLI1 (Hh/GLI1) and Wnt/β‐catenin pathways are crucial in cancer cell proliferation, survival, and drug resistance, making them significant targets for anticancer research. This study aimed to assess the effectiveness of combining inhibitors for both pathways against MCL and investigate the underlying molecular mechanisms. The co‐expression of key proteins from the Hh/GLI1 and Wnt/β‐catenin pathways was observed in MCL. Targeting the Hh/GLI1 pathway with the GLI1 inhibitor GANT61 and the Wnt/β‐catenin pathway with the CBP/β‐catenin transcription inhibitor ICG‐001, dual‐target therapy was demonstrated to synergistically suppressed the activity of MCL cells. This approach promoted MCL cell apoptosis, induced G0/G1 phase blockade, decreased the percentage of S‐phase cells, and enhanced the sensitivity of MCL cells to the drugs adriamycin and ibrutinib. Both GANT61 and ICG‐001 downregulated GLI1 and β‐catenin while upregulating GSK‐3β expression. The interaction between Hh/GLI1 and Wnt/β‐catenin pathways was mediated by GANT61‐dependent Hh/GLI1 inhibition. Moreover, GLI1 knockdown combined with ICG‐001 synergistically induced apoptosis and increased drug sensitivity of MCL cells to doxorubicin and ibrutinib. GANT61 attenuated the overexpression of β‐catenin and decreased the inhibition of GSK‐3β in MCL cells. Overall, the combined targeting of both the Hh/GLI1 and Wnt/β‐catenin pathways was more effective in suppressing proliferation, inducing G0/G1 cycle retardation, promoting apoptosis, and increasing drug sensitivity of MCL cells than mono treatments. These findings emphasize the potential of combinatorial therapy for treating MCL patients.

01 Sep 2024·Journal of Cellular Biochemistry

Conditioned Medium From Reactive Astrocytes Inhibits Proliferation, Resistance, and Migration of p53‐Mutant Glioblastoma Spheroid Through GLI‐1 Downregulation

Article

Author: Spohr, Tania Cristina Leite de Sampaio e ; Fernandes, Priscila Valverde ; Villarinho, Nícolas Jones ; Ribeiro, Jessica Honorato ; Lopes, Giselle Pinto de Faria

ABSTRACTGlioblastoma (GBM) aggressiveness is partly driven by the reactivation of signaling pathways such as Sonic hedgehog (SHH) and the interaction with its microenvironment. SHH pathway activation is one of the phenomena behind the glial transformation in response to tumor growth. The reactivation of the SHH signaling cascade during GBM–astrocyte interaction is highly relevant to understanding the mechanisms used by the tumor to modulate the adjacent stroma. The role of reactive astrocytes considering SHH signaling during GBM progression is investigated using a 3D in vitro model. T98G GBM spheroids displayed significant downregulation of SHH (61.4 ± 9.3%), GLI‐1 (6.5 ± 3.7%), Ki‐67 (33.7 ± 8.1%), and mutant MTp53 (21.3 ± 10.6%) compared to the CONTROL group when incubated with conditioned medium of reactive astrocytes (CM‐AST). The SHH pathway inhibitor, GANT‐61, significantly reduced previous markers (SHH = 43.0 ± 12.1%; GLI‐1 = 9.5 ± 3.4%; Ki‐67 = 31.9 ± 4.6%; MTp53 = 6.5 ± 7.5%) compared to the CONTROL, and a synergistic effect could be observed between GANT‐61 and CM‐AST. The volume (2.0 ± 0.2 × 107 µm³), cell viability (80.4 ± 3.2%), and migration (41 ± 10%) of GBM spheroids were significantly reduced in the presence of GANT‐61 and CM‐AST when compared to CM‐AST after 72 h (volume = 2.3 ± 0.4 × 107 µm³; viability = 92.2 ± 6.5%; migration = 102.5 ± 14.6%). Results demonstrated that factors released by reactive astrocytes promoted a neuroprotective effect preventing GBM progression using a 3D in vitro model potentiated by SHH pathway inhibition.

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Indication	Highest Phase	Country/Location	Organization	Date
Melanoma	Preclinical	JP	Health Sciences University of Hokkaido	16 May 2023

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