Sonic Hedgehog Medulloblastoma Cancer Stem Cells Mirnome and Transcriptome Highlight Novel Functional Networks

Pò, Agnese; Abballe, Luana; Sabato, Claudia; Gianno, Francesca; Chiacchiarini, Martina; Catanzaro, Giuseppina; Smaele, Enrico De; Giangaspero, Felice; Ferretti, Elisabetta; Miele, Evelina; Besharat, Zein Mersini

doi:10.3390/ijms19082326

Cited by 15 publications

(12 citation statements)

References 62 publications

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“…In mammals, three ligands have been identified in the Hh pathway: Sonic hedgehog (Shh), Desert hedgehog (Dhh) and Indian hedgehog (Ihh) [7]. Among these three ligands, Shh is the most thoroughly studied one, as well as the most important one [9,10]. Recently, the ectopic activation of the Shh pathway has been detected in a number of human malignancies [11,12].…”

Section: Ivyspringmentioning

confidence: 99%

Sonic Hedgehog/Gli1 Signaling Pathway Regulates Cell Migration and Invasion via Induction of Epithelial-to-mesenchymal Transition in Gastric Cancer

Ke¹,

Wang²,

Liu³

et al. 2020

J. Cancer

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Background:The aberrant activation of the Sonic hedgehog (Shh) signaling pathway is involved in progression of several types of cancer, including gastric cancer (GC). However, it remains uncertain whether it also plays a critical role in promoting cancer initiation and progression by inducing epithelial-to-mesenchymal transition (EMT) in GC. Thus, the aim of the present study was to determine whether the Shh pathway is involved in GC, and to investigate the function of the Shh pathway in the induction of EMT in GC. Materials and methods: The expression levels of Shh pathway members and EMT markers were examined in GC tissues by immunohistochemistry. The association between these factors and patient clinicopathological characteristics was analyzed. In addition, Gli-antagonist 61 (GANT61) was used to block Shh/Gli1 pathway activity, and recombinant Shh proteins (N-Shh) were used to activate the Shh pathway in GC cells. Wound healing and Transwell invasion and migration assays were performed to assess the effects of the Shh pathway on the migration and invasion of GC cells in vitro. Furthermore, western blot analysis was used to examine the changes in protein expression. Results: The results demonstrated that these Shh/Gli1 pathway members were upregulated in GC tissues, and that Gli1 upregulation was associated with tumor progression and a poor prognosis. Gli1 expression was negatively associated with E-cadherin (E-Cad) expression, and positively with Vimentin (VIM) expression in GC specimens. Further analysis revealed that when the Shh/Gli1 pathway was activated, the migratory and invasive abilities of GC cells were enhanced, and the expression levels of Gli1 and VIM were increased, while E-Cad expression was decreased. Opposite results were observed when the Shh/Gli1 pathway was blocked by GANT61. Conclusions: The present study indicated that the Shh/Gli1 pathway exhibits an abnormal activation pattern in GC with possible predictive and prognostic significance. The Shh/Gli1 pathway may promote the migratory and invasive potential of GC cells by inducing EMT. The Shh/Gli1 pathway can thus be considered as a potential therapeutic target for GC.

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Section: Ivyspringmentioning

confidence: 99%

Sonic Hedgehog/Gli1 Signaling Pathway Regulates Cell Migration and Invasion via Induction of Epithelial-to-mesenchymal Transition in Gastric Cancer

Ke¹,

Wang²,

Liu³

et al. 2020

J. Cancer

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“…We recently conducted small RNA and trascriptome sequencing on SHH MB CSCs and NSCs ( Besharat et al, 2018 ; Po et al, 2018 ). In this study, we focused on the EMT related RNAs that characterize SHH MB CSCs compared to NSCs, querying the differentially expressed transcripts listed in the EMT gene database dbEMT ( Zhao et al, 2015 ).…”

Section: Resultsmentioning

confidence: 99%

“…Three biological replicates of SHH MB CSCs were subjected to miRNA-sequencing or mRNA sequencing, quality control, mapping, quantification and differential expression analysis was performed between SHH MB CSCs and NSCs ( Besharat et al, 2018 ; Po et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

Low Expression of miR-466f-3p Sustains Epithelial to Mesenchymal Transition in Sonic Hedgehog Medulloblastoma Stem Cells Through Vegfa-Nrp2 Signaling Pathway

et al. 2018

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High-throughput analysis has improved the knowledge of medulloblastoma (MB), the leading cause of cancer related death in children, allowing a better comprehension of the key molecular pathways in MB pathogenesis. However, despite these advances, 30% of patients still die from the disease and survivors face severe long-term side effects. Cancer stem cells (CSCs) represent a subset of cells that not only drive tumorigenesis, but are also one of the main determinants of chemoresistance. Epithelial mesenchymal transition (EMT) is a hallmark of cancer and up to now few data is available in MB. To give insight into the role of the EMT process in maintaining the mesenchymal phenotype of CSCs, we analyzed the expression of EMT related transcripts and microRNAs in these cells. We firstly isolated CSCs from Sonic Hedgehog (SHH) MB derived from Ptch1 heterozygous mice and compared their expression level of EMT-related transcripts and microRNAs with cerebellar NSCs. We identified two molecules linked to SHH and EMT, Vegfa and its receptor Nrp2, over-expressed in SHH MB CSCs. Inhibition of Vegfa showed impairment of cell proliferation and self-renewal ability of CSCs concurrent with an increase of the expression of the EMT gene, E-cadherin, and a decrease of the EMT marker, Vimentin. Moreover, among deregulated microRNAs, we identified miR-466f-3p, a validated inhibitor of both Vegfa and Nrp2. These results allowed us to describe a new EMT molecular network, involving the down-regulation of miR-466f-3p together with the concordant up-regulation of Vegfa and Nrp2, that sustains the mesenchymal phenotype of SHH MB CSCs.

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“…Among the other drivers of the SHH pathway is the protein patched homolog 1 (Ptch) 103–105. A single tumour mouse model, namely the Ptch +/− model, has long been used to study the molecular and cellular mechanisms involved in MB formation, particularly MB SHH 106 107.…”

Section: Mb-cscs: From Genes To Therapiesmentioning

confidence: 99%

Medulloblastoma cancer stem cells: molecular signatures and therapeutic targets

Bahmad

Poppiti

2020

J Clin Pathol

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Medulloblastoma (MB) is the most common malignant primary intracranial neoplasm diagnosed in childhood. Although numerous efforts have been made during the past few years to exploit novel targeted therapies for this aggressive neoplasm, there still exist substantial hitches hindering successful management of MB. Lately, progress in cancer biology has shown evidence that a subpopulation of cells within the tumour, namely cancer stem cells (CSCs), are thought to be responsible for the resistance to most chemotherapeutic agents and radiation therapy, accounting for cancer recurrence. Hence, it is crucial to identify the molecular signatures and genetic aberrations that characterise those CSCs and develop therapies that specifically target them. In this review, we aim to give an overview of the main genetic and molecular cues that depict MB-CSCs and provide a synopsis of the novel therapeutic approaches that specifically target this population of cells to attain enhanced antitumorous effects and therefore overcome resistance to therapy.

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Sonic Hedgehog Medulloblastoma Cancer Stem Cells Mirnome and Transcriptome Highlight Novel Functional Networks

Cited by 15 publications

References 62 publications

Sonic Hedgehog/Gli1 Signaling Pathway Regulates Cell Migration and Invasion via Induction of Epithelial-to-mesenchymal Transition in Gastric Cancer

Sonic Hedgehog/Gli1 Signaling Pathway Regulates Cell Migration and Invasion via Induction of Epithelial-to-mesenchymal Transition in Gastric Cancer

Low Expression of miR-466f-3p Sustains Epithelial to Mesenchymal Transition in Sonic Hedgehog Medulloblastoma Stem Cells Through Vegfa-Nrp2 Signaling Pathway

Medulloblastoma cancer stem cells: molecular signatures and therapeutic targets

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