Snail is critical for tumor growth and metastasis of ovarian carcinoma

Jin, Huajun; Yang, Yu Shih; Zhang, Tao; Zhou, Xingyu; Zhou, Jiayi; Jia, Luoqi; Wu, Yadi; Zhou, Binhua P.; Feng, Yi

doi:10.1002/ijc.24901

Cited by 135 publications

(107 citation statements)

References 33 publications

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“…Snail regulates the expression of several genes mainly involved in cell invasion and migration including matrix metalloproteinase (MMP) family members (MMP1, MMP2, and MMP7) and cell-cell or cell-matrix interacting proteins (E-cadherin, integrin-a6, and tissue inhibitor of metalloproteinase 3; ref. 48). Furthermore, this factor is responsible for suppressing the expression of other genes including caspase-8 and tumor-suppressor CYLD (49).…”

Section: Discussionmentioning

confidence: 99%

PAK1 Tyrosine Phosphorylation Is Required to Induce Epithelial–Mesenchymal Transition and Radioresistance in Lung Cancer Cells

et al. 2014

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The p21-activated Ser/Thr kinase 1 (PAK1) kinase has an essential role in tumorigenesis and cell survival in many cancers, but its regulation is not fully understood. In this study, we showed that in response to irradiation of lung cancer cells, PAK1 was upregulated, tyrosine phosphorylated, and translocated to the nucleus. Tyrosine phosphorylation relied upon JAK2 kinase activity and was essential for PAK1 protein stability and binding to Snail. This radiation-induced JAK2-PAK1-Snail signaling pathway increased epithelial-mesenchymal transition (EMT) by regulating epithelial and mesenchymal cell markers. Notably, JAK2 inhibitors mediated radiosensitization and EMT blockade in a mouse xenograft model of lung cancer. Taken together, our findings offered evidence that JAK2 phosphorylates and stabilizes functions of PAK1 that promote EMT and radioresistance in lung cancer cells, with additional implications for the use of JAK2 inhibitors as radiosensitizers in lung cancer treatment.

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Section: Discussionmentioning

confidence: 99%

PAK1 Tyrosine Phosphorylation Is Required to Induce Epithelial–Mesenchymal Transition and Radioresistance in Lung Cancer Cells

et al. 2014

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“…Snail is a key inducer of EMT and functions as a negative regulator of E-cadherin transcription. Several studies have demonstrated that nuclear localization of Snail correlates with tumor progression, with enhanced Snail immunoreactivity in metastatic lesions (70,71). Furthermore, patients with both primary and metastatic tumors positive for Snail expression showed a significant decrease in overall survival (72).…”

Section: Discussionmentioning

confidence: 99%

Integrin Regulation of β-Catenin Signaling in Ovarian Carcinoma

Burkhalter

Symowicz

Hudson

et al. 2011

Journal of Biological Chemistry

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Reversible modulation of integrin-regulated cell-matrix adhesion and epithelial (E)-cadherin-mediated cell-cell adhesion plays a critical role in the establishment of ovarian cancer metastases. In contrast to most epithelial cell-derived tumors that down-regulate E-cadherin expression during progression, acquisition of E-cadherin expression accompanies malignant transformation of the ovarian surface epithelium and is maintained in peritoneal metastases. Metastatic epithelial ovarian cancer cells are disseminated intraperitoneally and preferentially adhere via integrins to interstitial collagens in the peritoneal cavity. This study was undertaken to determine whether integrin engagement influences E-cadherin and ␤-catenin localization and function. The data demonstrate that multivalent integrin engagement results in increased internalization of E-cadherin, inhibition of GSK-3␤, elevated levels of nuclear ␤-catenin, increased ␤-catenin-regulated promoter activation, and transcriptional activation of Wnt/␤-catenin target genes. Blocking ␤-catenin transcriptional control with inhibitor of ␤-catenin and Tcf-4 reduces cellular invasion, suggesting a key role for ␤-catenin nuclear signaling in EOC invasion and metastasis. These studies support a model wherein cell-matrix engagement regulates the functional integrity of cell-cell contacts, leading to increased ␤-catenin nuclear signaling and enhanced cellular invasive activity. Furthermore, these results provide a mechanism for activation of Wnt/␤-catenin signaling in the absence of activating mutations in this pathway.Epithelial (E) 3 -cadherin is a single-span transmembrane glycoprotein that mediates calcium-dependent cell-cell adhesion via interaction with the extracellular domains of cadherins on the surface of neighboring cells (1, 2). Key functions of E-cadherin include the regulation of cell polarity and the maintenance of epithelial organization (3). Although most normal epithelia express high levels of E-cadherin, this cadherin is absent in the mesenchymally derived normal ovarian surface epithelium, which expresses neural (N)-cadherin. In most carcinomas, E-cadherin expression is down-regulated or lost, facilitating cellular dispersal, invasion, and metastasis (4). However, a unique feature of EOC is that E-cadherin becomes more abundant in primary differentiated carcinomas, with all histotypes displaying strong immunoreactivity (reviewed in Refs. 5, 6). There is less clarity regarding relative E-cadherin levels during ovarian tumor progression and metastasis. Although complete loss of E-cadherin is uncommon, reduced staining is often detected in late stage tumors and in ascites-derived tumor cells (7-9), and negative E-cadherin is predictive of poor overall survival (10, 11).␤-Catenin is found predominantly in association with the E-cadherin cytoplasmic domain at cell-cell junctions (12). In the absence of cell-cell contact and Wnt signaling, cytosolic ␤-catenin forms a complex with adenomatous poliosis coli, Axin/conductin, casein kinases 1␣ and 1⑀, and glyc...

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“…Although MMP2 and MMP9 have been widely accepted as accelerators of cancer metastasis in OSCC, the molecular mechanisms underlying their up-regulation by the Snail family remain unclear (28). It seems that MMP9 can be regulated by both Snail and Slug (22,27), but there are few reports of their effects on MMP2.…”

Section: Discussionmentioning

confidence: 99%

Epithelial-mesenchymal transition in oral squamous cell carcinoma triggered by transforming growth factor-β1 is Snail family-dependent and correlates with matrix metalloproteinase-2 and -9 expressions

Qiao

Johnson²,

Gao³

2010

Int J Oncol

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Abstract. Snail and Slug play important roles in cancer progression by promoting epithelial-mesenchymal transition (EMT). Although Snail is well studied, its role in oral squamous cell carcinoma (OSCC) and its regulatory relationship with Slug remain unclear. We aimed to determine whether Snail and Slug interplay occurs in transforming growth factor-ß1 (TGF-ß1)-initiated EMT of OSCC cells, and to assess the expression of matrix metalloproteinases (MMPs) in this process. Three OSCC cell lines, SCC9, SCC15 and SCC25 were treated with recombinant TGF-ß1 for 0-6 days. Activities of the EMT regulators, Snail and Slug, and of extracellular hallmarks, MMP2 and 9, were detected using real-time PCR and Western blots. An in vitro wound healing assay then assessed short-term EMT, whilst phenotypic changes associated with the above gene expressions were evaluated by immunocytochemistry. Results showed that Slug and MMP9 were up-regulated at both mRNA and protein levels, while Snail expression rose and fell, in concert with expression of MMP2. In the wound healing assay, Snail was seen alone at the invasive front in SCC9 and SCC15 cultures, while both Snail and Slug appeared at wound margins in SCC25. Both MMP2 and MMP9 were detected at wound edges in all cell lines, with MMP2 localised in cell nuclei, MMP9 was restricted to the cytoplasm. The study suggests that both Snail and Slug act as regulators of TGF-ß1-trigged EMT in OSCC cells. Snail may up-regulate MMP2 or MMP9 initiating EMT, while Slug may share a role with Snail in maintaining longer-term EMT, by stimulating MMP9 expression.

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Snail is critical for tumor growth and metastasis of ovarian carcinoma

Cited by 135 publications

References 33 publications

PAK1 Tyrosine Phosphorylation Is Required to Induce Epithelial–Mesenchymal Transition and Radioresistance in Lung Cancer Cells

PAK1 Tyrosine Phosphorylation Is Required to Induce Epithelial–Mesenchymal Transition and Radioresistance in Lung Cancer Cells

Integrin Regulation of β-Catenin Signaling in Ovarian Carcinoma

Epithelial-mesenchymal transition in oral squamous cell carcinoma triggered by transforming growth factor-β1 is Snail family-dependent and correlates with matrix metalloproteinase-2 and -9 expressions

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