Sonic hedgehog–Gli1 signals promote epithelial–mesenchymal transition in ovarian cancer by mediating PI3K/AKT pathway

Zhang, Ke; Sun, Chenglin; Zhang, Qing; Wang, Xiaojing

doi:10.1007/s12032-014-0368-y

Cited by 72 publications

(65 citation statements)

References 18 publications

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“…Another possible explanation for the nuclear GLI1 localization could rest on the role of non‐canonical pathways of HH signaling. GLI transcription factors have been shown to be positively regulated by K‐Ras and PI3K‐AKT, and negatively regulated by p53 . As dysfunctions of these molecules are reported to promote the development of cutaneous SCC, it is plausible that some cutaneous SCC, including in situ lesions, have nuclear localization of GLI1.…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical visualization of the signature of activated Hedgehog signaling pathway in cutaneous epithelial tumors

Tanese

Emoto

Kubota

et al. 2018

The Journal of Dermatology

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Activation of the Hedgehog (HH) signaling pathway plays a critical role in the development of basal cell carcinoma (BCC). HH signaling activity is produced by nuclear translocation of transcription factors, glioma-associated oncogene homolog (GLI). Among three GLI subfamilies, GLI1 is the only full-length transcriptional activator, and its nuclear localization is recognized as a signature event in HH signaling activation. However, limited published work has investigated the nuclear staining of GLI1 protein in human tumor tissue samples by immunohistochemical analysis. In this study, we performed immunohistochemical staining of GLI1 in 382 cases of cutaneous epithelial tumors, including 196 BCC cases, using rabbit monoclonal antihuman GLI1 antibody (C68H3). As a result, 98.2% cases of BCC showed a diffuse and strong nuclear staining pattern regardless of the histological subtype. Positive staining was mainly restricted to the tumor nests, while the overlying epidermis was negative suggesting specificity of the antibody. In further analysis of other cutaneous epithelial tumors, 100% (4/4) cases of trichoblastoma, 15.1% (5/33) Bowen's disease, 3.5% (1/28) actinic keratosis and 12.5% (4/32) squamous cell carcinoma showed the nuclear staining pattern of GLI1. This suggested that HH signaling is also dysregulated in some other cutaneous malignant tumors. In conclusion, the C68H3 antibody is a useful tool for revealing activation of HH signaling in immunohistochemical analysis.

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Section: Discussionmentioning

confidence: 99%

Immunohistochemical visualization of the signature of activated Hedgehog signaling pathway in cutaneous epithelial tumors

Tanese

Emoto

Kubota

et al. 2018

The Journal of Dermatology

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“…In the last decades, EMT has been extensively studied and validated in the progression of various carcinomas such as HCC [23,24]. A large body of researches has claimed the important role of EMT in facilitating tumor development and progression by driving metastasis, through the acquisition of enhanced migratory and invasive potential [25][26][27][28][29][30]. Metastasis, induced by EMT, deconvoluted into several steps including intravasation, circulation, margination, extravasation and colonization, is a crucial cause of deaths in cancer therapy [31,32].…”

Section: Epithelial-mesenchymal Transitions (Emt)mentioning

confidence: 99%

Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma

et al. 2015

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“…The data regarding the crosstalk between HER2 and Hh signaling in BC are very limited. However, it is reported that HER2 downstream pathways PI3K/AKT and MAPK interact with Hh signaling pathway in regulating tumorigenesis and stemness in chronic lymphocytic leukemia [300], ovarian [301], pancreatic [302] and esophageal [303] cancers.…”

Section: Her2 Promotes Stemness Signaling Pathwaysmentioning

confidence: 99%

HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance

Nami

Wang

2017

Cancers

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HER2 receptor tyrosine kinase that is overexpressed in approximately 20% of all breast cancers (BCs) is a poor prognosis factor and a precious target for BC therapy. Trastuzumab is approved by FDA to specifically target HER2 for treating HER2+ BC. However, about 60% of patients with HER2+ breast tumor develop de novo resistance to trastuzumab, partially due to the loss of expression of HER2 extracellular domain on their tumor cells. This is due to shedding/cleavage of HER2 by metalloproteinases (ADAMs and MMPs). HER2 shedding results in the accumulation of intracellular carboxyl-terminal HER2 (p95HER2), which is a common phenomenon in trastuzumab-resistant tumors and is suggested as a predictive marker for trastuzumab resistance. Up-regulation of the metalloproteinases is a poor prognosis factor and is commonly seen in mesenchymal-like cancer stem cells that are risen during epithelial to mesenchymal transition (EMT) of tumor cells. HER2 cleavage during EMT can explain why secondary metastatic tumors with high percentage of mesenchymal-like cancer stem cells are mostly resistant to trastuzumab but still sensitive to lapatinib. Importantly, many studies report HER2 interaction with oncogenic/stemness signaling pathways including TGF-β/Smad, Wnt/β-catenin, Notch, JAK/STAT and Hedgehog. HER2 overexpression promotes EMT and the emergence of cancer stem cell properties in BC. Increased expression and activation of metalloproteinases during EMT leads to proteolytic cleavage and shedding of HER2 receptor, which downregulates HER2 extracellular domain and eventually increases trastuzumab resistance. Here, we review the hypothesis that a negative feedback loop between HER2 and stemness signaling drives resistance of BC to trastuzumab.

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Sonic hedgehog–Gli1 signals promote epithelial–mesenchymal transition in ovarian cancer by mediating PI3K/AKT pathway

Cited by 72 publications

References 18 publications

Immunohistochemical visualization of the signature of activated Hedgehog signaling pathway in cutaneous epithelial tumors

Immunohistochemical visualization of the signature of activated Hedgehog signaling pathway in cutaneous epithelial tumors

Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma

HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance

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