A dual mechanism of activation of the Sonic Hedgehog pathway in anaplastic thyroid cancer: crosstalk with RAS-BRAF-MEK pathway and ligand secretion by tumor stroma

Parascandolo, Alessia; Laukkanen, Mikko O.; Rosa, Nancy De; Ugolini, Clara; Cantisani, Maria Carmela; Cirafici, Anna Maria; Basolo, Fulvio; Santoro, Massimo; Castellone, Maria Domenica

doi:10.18632/oncotarget.23388

Cited by 19 publications

(16 citation statements)

References 38 publications

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“…The most common structural aberration, gain/ amplification of the fragment of the chromosome 12p, was present in 3/13 samples. None of the other CNAs either observed in our study or reported previously was seen consistently [19,23,36,45]. In the previously published pilot study [25], we have identified only two recurrent aberrations, namely gains at 12p13.33p11.1 and 17q11.1q25.3.…”

Section: Discussionsupporting

confidence: 59%

“…These include overexpression of SMO, GLI1 and other regulatory enhancers or decreased/ silenced expression or aberrant function of PTCH1, SUFU, and cooperating repressors. Important in oncogenic signalling are crosstalks with transforming growth factor β (TGF-β)/BMP, WNT, Hippo, EGFR, K-Ras, PKA, Notch, PKC, Mek1, GSK3B, PI3K and other systems [19,35,36]. Therefore, a whole-genome screening approach with using the microarray-CGH technique was applied in the current report to evaluate the signs of alterations at various points of the pathway in the examined group of intracranial paediatric GCTs.…”

Section: Discussionmentioning

confidence: 99%

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Hedgehog signalling network gene status analysis in paediatric intracranial germ cell tumours

Kuleszo

Lipska‐Ziętkiewicz

Koczkowska

et al. 2019

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Introduction: Germ cell tumours (GCTs) in the children comprise a group of tumours that originate from primordial germ cells but their pathogenesis is not clear. Intracranial GCTs represent a special subset of these paediatric neoplasms. Hedgehog (Hh) pathway gene status in GCTs is generally unexplored, while Hh signalling is involved in germ cell biology. Material and methods: Comparative genomic profiling analysis with a microarray-comparative genomic hybridization (CGH) + single nucleotide polymorphism (SNP) technique in a group of intracranial paediatric GCTs was performed. The analysis included evaluation of genes being ligands, receptors, regulators, effectors, and targets of Hh signalling. Results: Chromosomal aberrations were found in 62% of examined tumours, showing their heterogeneity. A number of private genomic imbalances were observed, but only a few recurrent ones. The most common numerical changes were trisomies 19, 21 and monosomies 13, 18 while the most frequent structural aberration was gain/ amplification of the chromosome 12p. The analysis of the gene status of Hh network elements showed imbalances in a proportion of tumours. PTCH1, GLI2, IHH and ZIC2 gene aberrations occurred most frequently. Moreover, six tumours had various copy gains or losses of several other genes involved in the pathway, including HHIP, GLI1, GLI3, DHH, SHH, SMO, PTCH2, and several genes from the WNT group. Interestingly, four cases showed losses of pathway repressors, with parallel gains of activators in two of them. Correlations with patho-clinical tumour features were not found, most probably due to the heterogeneity of the examined limited group. Conclusions: Our results show few genomic alterations related to the Hh signalling pathway genes in paediatric intracranial GCTs. Further analysis of Hedgehog pathway alterations can potentially disclose its biological significance and define new prognostic factors and/or therapeutic targets for high-risk patients.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Hedgehog signalling network gene status analysis in paediatric intracranial germ cell tumours

Kuleszo

Lipska‐Ziętkiewicz

Koczkowska

et al. 2019

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“…Female mice seem to be more sensitive towards the effect of Hh signalling in terms of energy metabolism. These findings should be considered, as therapeutic treatments targeting the Hh pathway seem to be a promising therapy for different cancer types [54,55]. The sex-specific effect of Hh inhibitors on energy metabolism could make a difference in the survival of male and female patients, which is often reduced by aggressive therapies.…”

Section: Discussionmentioning

confidence: 99%

Cyclopamine and Rapamycin Synergistically Inhibit mTOR Signalling in Mouse Hepatocytes, Revealing an Interaction of Hedgehog and mTor Signalling in the Liver

Spormann

Rennert

Kolbe

et al. 2020

Cells

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In the liver, energy homeostasis is mainly regulated by mechanistic target of rapamycin (mTOR) signalling, which influences relevant metabolic pathways, including lipid metabolism. However, the Hedgehog (Hh) pathway is one of the newly identified drivers of hepatic lipid metabolism. Although the link between mTOR and Hh signalling was previously demonstrated in cancer development and progression, knowledge of their molecular crosstalk in healthy liver is lacking. To close this information gap, we used a transgenic mouse model, which allows hepatocyte-specific deletion of the Hh pathway, and in vitro studies to reveal interactions between Hh and mTOR signalling. The study was conducted in male and female mice to investigate sexual differences in the crosstalk of these signalling pathways. Our results reveal that the conditional Hh knockout reduces mitochondrial adenosine triphosphate (ATP) production in primary hepatocytes from female mice and inhibits autophagy in hepatocytes from both sexes. Furthermore, in vitro studies show a synergistic effect of cyclopamine and rapamycin on the inhibition of mTor signalling and oxidative respiration in primary hepatocytes from male and female C57BL/6N mice. Overall, our results demonstrate that the impairment of Hh signalling influences mTOR signalling and therefore represses oxidative phosphorylation and autophagy.

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“…Actually, the expression of GLIs could be regulated through a SMO-independent pathway. A series of factors such as oncogenic receptor tyrosine kinases, RAS/MAP kinase, PI3K/AKT/S6K, DYRK1A, PKC, TGF-β, and histone deacetylases could enhance the transcriptional activity of GLIs in human cancer cells 34,35 . It was well documented that TGF-β always acted as a key player in epithelial–mesenchymal transition (EMT)-mediated tumor metastasis and therapy resistance in LUADs, which might be the likely mediator to modulate the transcription of GLIs 36 .…”

Section: Discussionmentioning

confidence: 99%

Regulating autophagy facilitated therapeutic efficacy of the sonic Hedgehog pathway inhibition on lung adenocarcinoma through GLI2 suppression and ROS production

et al. 2019

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Lung adenocarcinoma (LUAD), which comprises over 50% of all cases of non-small-cell lung cancer, has a poor prognosis and requires novel therapeutic approaches. The sonic Hedgehog (Shh) pathway, which plays a crucial role in differentiation, proliferation, and survival of cancer cells, is likely to be activated in LUADs, suggesting the Shh pathway as a potential therapeutic target for LUAD treatment. In this study, we reported that vismodegib, an inhibitor of the Shh pathway, only elicited minor antitumor efficacy in A549 and NCI-H1975 LUAD cells as well as in the xenograft tumors, with overexpressed GLI2 and increased autophagic activity. The aberrant autophagy in LUAD cells was further confirmed by the three main stages of autophagic flux, including the formation of autophagosomes, the fusion of autophagosomes with lysosomes, and degradation of autophagosomes in lysosomes. Furthermore, inhibition of autophagy by siRNA against ATG5 or ATG7 rescued the sensitivity of A549 and NCI-H1975 LUAD cells to vismodegib in vitro. Meanwhile, administration of the pharmaceutical inhibitor of autophagy, chloroquine, contributed to the enhanced anti-LUAD efficacy of vismodegib in vivo, probably through overproduction of ROS, acceleration of apoptosis, and suppression of GLI2 in LUAD tissues. In summary, our research revealed that downregulating autophagy facilitated the anti-LUAD efficacy of the Shh pathway suppression, thus highlighting a potential approach for LUAD therapy via simultaneously targeting the Shh signaling and autophagy pathway.

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A dual mechanism of activation of the Sonic Hedgehog pathway in anaplastic thyroid cancer: crosstalk with RAS-BRAF-MEK pathway and ligand secretion by tumor stroma

Cited by 19 publications

References 38 publications

Hedgehog signalling network gene status analysis in paediatric intracranial germ cell tumours

Hedgehog signalling network gene status analysis in paediatric intracranial germ cell tumours

Cyclopamine and Rapamycin Synergistically Inhibit mTOR Signalling in Mouse Hepatocytes, Revealing an Interaction of Hedgehog and mTor Signalling in the Liver

Regulating autophagy facilitated therapeutic efficacy of the sonic Hedgehog pathway inhibition on lung adenocarcinoma through GLI2 suppression and ROS production

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