Targeting of sonic hedgehog-Gli signaling: A potential therapeutic target for patients with breast cancer

Song, Lingqin; Wang, Weifeng; Liu, Di; Zhao, Yang; He, Jing; Wang, Xijing; Dai, Zhijun; Zhang, Huimin; Li, Xiao

doi:10.3892/ol.2016.4722

Cited by 17 publications

(14 citation statements)

References 39 publications

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“…The Shh signaling pathway plays crucial roles in regulating cell differentiation, adhesion, migration, transformation, and apoptosis [ 19 ]. It was found that Shh signaling was activated in many human cancers such as gastric cancer, liver cancer, breast cancer, and ovarian cancer [ 11 , 20 ]. Moreover, activation of Shh signaling was found to be highly associated with increased capacities of chemoresistance and radioresistance in human malignant tumors [ 21 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…Then Smo perform translocation and thereby activates downstream transcriptional factors of the glioma-associated oncogene homolog (Gli) family to which Shh belongs, including Gli1, Gli2, and Gli3 [ 10 ]. Gli1 is the most important member, which translocates to the nucleus after activation and further initiates transcription of target genes regulating cell cycle, apoptosis, migration, and signaling transductions [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Activation of Sonic Hedgehog Signaling Is Associated with Human Osteosarcoma Cells Radioresistance Characterized by Increased Proliferation, Migration, and Invasion

Qü

Wang

et al. 2018

Med Sci Monit

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BackgroundRadioresistance restricts the application of radiotherapy in human osteosarcoma (OS). This study investigated the molecular mechanism of radioresistance in OS, which may provide clues to finding ideal targets for genetic therapy.Materila/MethodsThe human OS cell line MG63 was employed as parent cells. After repeat low-dose X-ray irradiation of MG63, the radioresistant OS cell line MG63R was produced. Colony formation assay was used to assess the radioresistance. Cell viability was evaluated by CCK-8 assay. Flow cytometry was used to detect cell apoptosis, and wound healing assay was used to evaluate invasive capacity. The nuclear translocation was evaluated by fluorescent immunohistochemistry. Protein expression levels were assessed by Western blotting. Specific siRNA against Shh was used to silence Shh.ResultsMore survival colony formation, elevated cell viability, less cell apoptosis, and increased wound closure were found in MG63R than in MG63 cells exposed to irradiation. The nuclear translocation of Gli, expression levels of Shh, Smo, Ptch1, Bcl2, active MMP2, and active MMP9 were increased in MG63R cells compared with MG63 cells. Transfection of Shh-siRNA suppressed expression levels of Shh, Smo, Ptch1, Bcl2, active MMP2, and active MMP9, as well as the nuclear translocation of Gli in MG63R cells. The cell viability, survival colony formation, and wound closure were impaired, whereas cell apoptosis was increased, in siRNA-transfected MG63R cells than in control MG63R cells exposed to irradiation.ConclusionsActivation of Shh signaling was involved in radioresistance of OS cells. Blocking this signaling can impair the radioresistance capacity of OS cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Activation of Sonic Hedgehog Signaling Is Associated with Human Osteosarcoma Cells Radioresistance Characterized by Increased Proliferation, Migration, and Invasion

Qü

Wang

et al. 2018

Med Sci Monit

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“…Aberrant activation of the Sonic hedgehog (Shh; the vertebrate counterpart of Hh) signaling pathway has been implicated in initiation, progression, and metastatic invasion of multiple cancer types (Evangelista et al 2006;Song et al 2016). While deregulated Shh signaling upregulates levels of different components of cell-cycle machinery leading to unrestricted proliferation of cancer cells (Kenney and Rowitch 2000;Mille et al 2014), Shh signaling also promotes metastasis through induced expression of MMP-2 and MMP-9 (Wang et al 2015).…”

Section: Discussionmentioning

confidence: 99%

Noncanonical Decapentaplegic Signaling Activates Matrix Metalloproteinase 1 To Restrict Hedgehog Activity and Limit Ectopic Eye Differentiation in Drosophila

et al. 2017

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One of the pertinent issues associated with cellular plasticity is to understand how the delicate balance between the determined state of cells and the extent to which they can transdetermine is maintained. Employing the well-established model of generating ectopic eyes in developing wing discs of by ectopic expression, we provide evidence for the genetic basis of this mechanism. By both loss-of-function and gain-of-function genetic analyses, we demonstrate that Matrix metalloproteinase 1 (Mmp1) plays an important role in regulating the extent of ectopic ommatidial differentiation. Transcriptional activation of ectopic Mmp1 by the morphogen Decapentaplegic (Dpp) is not triggered by its canonical signaling pathway which involves Mad. Rather, Dpp activates an alternate cascade involving dTak1 and JNK, to induce ectopic Mmp1 expression. Mutational analyses reveal that Mmp1 negatively regulates ectopic eye differentiation by restricting the rate of proliferation and the levels of expression of retinal-determining genes and This is primarily achieved by restricting the range of Hedgehog (Hh) signaling. Importantly, the increase in proliferation and upregulation of target retinal-determining genes, as observed upon attenuating Mmp1 activity, gets significantly rescued when ectopic eyes are generated in wing discs of heterozygous mutants. In conjunction with the previously established instructive and permissive roles of Dpp in facilitating ectopic eye differentiation in wing discs, the outcome of this study sheds light on a mechanism by which Dpp plays a dual role in modulating the delicate balance between the determined state of cells and the extent they can transdetermine.

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“…In MDA-MB-231 TNBC cells, a marked increase in the levels of the activated Sonic Hh (SHh), Ptch, Smo and Gli1 resulted in overexpression of Bcl2 and cyclin D1, thereby contributing to cell proliferation and survival [ 305 ]. Cyclopamine treatment in these cells resulted in a decrease in Gli mRNA and cell viability which correlated with the cyclopamine treatment-associated decrease in Bcl2 and cyclin D1 [ 305 ]. Additionally, exposure of MDA-MB-231 cells to human SHh significantly reduced the levels of E-cadherin, increased MMP2 and MMP9, and enhanced cell migration and invasion, thereby contributing to EMT.…”

Section: Phytochemicals As Anticancer Compounds Effective In the Tmentioning

confidence: 99%

“…Additionally, exposure of MDA-MB-231 cells to human SHh significantly reduced the levels of E-cadherin, increased MMP2 and MMP9, and enhanced cell migration and invasion, thereby contributing to EMT. This effect was reversed, and levels of E-cadherin were enhanced, while the levels of MMP2 and MMP9 decreased in cyclopamine treated cells, with a consequent decrease in cell migration and invasion [ 305 ]. Cyclopamine treatment showed significant suppression of proliferation in MCF-7 and MDA-MB-231 breast cancer cells, caused by a robust G1 cell cycle arrest and inhibition of MAPK/ERK signaling which contributed to the decrease in the expression of cyclin D1 [ 188 ].…”

Section: Phytochemicals As Anticancer Compounds Effective In the Tmentioning

confidence: 99%

The “Yin and Yang” of Natural Compounds in Anticancer Therapy of Triple-Negative Breast Cancers

Varghese

Samuel

Abotaleb

et al. 2018

Cancers

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Among the different types of breast cancers, triple-negative breast cancers (TNBCs) are highly aggressive, do not respond to conventional hormonal/human epidermal growth factor receptor 2 (HER2)-targeted interventions due to the lack of the respective receptor targets, have chances of early recurrence, metastasize, tend to be more invasive in nature, and develop drug resistance. The global burden of TNBCs is increasing regardless of the number of cytotoxic drugs being introduced into the market each year as they have only moderate efficacy and/or unforeseen side effects. Therefore, the demand for more efficient therapeutic interventions, with reduced side effects, for the treatment of TNBCs is rising. While some plant metabolites/derivatives actually induce the risk of cancers, many plant-derived active principles have gained attention as efficient anticancer agents against TNBCs, with fewer adverse side effects. Here we discuss the possible oncogenic molecular pathways in TNBCs and how the purified plant-derived natural compounds specifically target and modulate the genes and/or proteins involved in these aberrant pathways to exhibit their anticancer potential. We have linked the anticancer potential of plant-derived natural compounds (luteolin, chalcones, piperine, deguelin, quercetin, rutin, fisetin, curcumin, resveratrol, and others) to their ability to target multiple dysregulated signaling pathways (such as the Wnt/β-catenin, Notch, NF-κB, PI3K/Akt/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK) and Hedgehog) leading to suppression of cell growth, proliferation, migration, inflammation, angiogenesis, epithelial-mesenchymal transition (EMT) and metastasis, and activation of apoptosis in TNBCs. Plant-derived compounds in combination with classical chemotherapeutic agents were more efficient in the treatment of TNBCs, possibly with lesser side effects.

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Targeting of sonic hedgehog-Gli signaling: A potential therapeutic target for patients with breast cancer

Cited by 17 publications

References 39 publications

Activation of Sonic Hedgehog Signaling Is Associated with Human Osteosarcoma Cells Radioresistance Characterized by Increased Proliferation, Migration, and Invasion

Activation of Sonic Hedgehog Signaling Is Associated with Human Osteosarcoma Cells Radioresistance Characterized by Increased Proliferation, Migration, and Invasion

Noncanonical Decapentaplegic Signaling Activates Matrix Metalloproteinase 1 To Restrict Hedgehog Activity and Limit Ectopic Eye Differentiation in Drosophila

The “Yin and Yang” of Natural Compounds in Anticancer Therapy of Triple-Negative Breast Cancers

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