Stanniocalicin 2 Suppresses Breast Cancer Cell Migration and Invasion via the PKC/Claudin-1-Mediated Signaling

Hou, Jing; Wang, Ziliang; Xu, Han; Yang, Lina; Yu, Xiaoli; Yang, Zhaozhi; Deng, Yun; Meng, Jiao; Yan, Feng; Guo, Xiaomao; Yang, Gong

doi:10.1371/journal.pone.0122179

Cited by 52 publications

(52 citation statements)

References 40 publications

(46 reference statements)

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“…However, given its role in promoting lymphovascular invasion and regional metastasis, other studies have shown that Snail may also be used as a molecular prognostic marker for HNSCC [41, 42]. Although Hou et al reported that STC2 may inhibit EMT in human breast cancer cells [43], our results suggest that the interaction between Snail and the PI3K/AKT pathway may mediate STC2-induced HNSCC metastasis. Similarly, the expression patterns of STC2, pAKT, Snail, vimentin, and E-cadherin in HNSCC tissues were consistent with those in cells, implying that STC2 plays an oncogenic role in HNSCC.…”

Section: Discussionmentioning

confidence: 53%

STC2 promotes head and neck squamous cell carcinoma metastasis through modulating the PI3K/AKT/Snail signaling

Yang

Ji²,

Chang

et al. 2016

Oncotarget

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The mammalian peptide hormone stanniocalcin 2 (STC2) plays an oncogenic role in many human cancers. However, the exact function of STC2 in human head and neck squamous cell carcinoma (HNSCC) is unclear. We aimed to examine the function and clinical significance of STC2 in HNSCC. Using in vitro and in vivo assays, we show that overexpression of STC2 suppressed cell apoptosis, promoted cell proliferation, migration, invasion, and cell cycle arrest at the G1/S transition. By contrast, silencing of STC2 inhibited these activities. We further show that STC2 upregulated the phosphorylation of AKT and enhanced HNSCC metastasis via Snail-mediated increase of vimentin and decrease of E-cadherin. These responses were blocked by silencing of STC2/Snail expression or inhibition of pAKT activity. Furthermore, clinical data indicate that high STC2 expression was associated with high levels of pAKT and Snail in tumor samples from HNSCC patients with regional lymph node metastasis (P < 0.01). Thus, we conclude that STC2 controls HNSCC metastasis via the PI3K/AKT/Snail signaling axis and that targeted therapy against STC2 may be a novel strategy to effectively treat patients with metastatic HNSCC.

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Section: Discussionmentioning

confidence: 53%

STC2 promotes head and neck squamous cell carcinoma metastasis through modulating the PI3K/AKT/Snail signaling

Yang

Ji²,

Chang

et al. 2016

Oncotarget

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“…STC2, a secreted glycoprotein hormone expressed by a variety of tissues, regulates calcium and phosphate homeostasis, inhibits apoptosis and oxidative damage, and induces proliferation [43,44]. STC2 has recently been described to inhibit epithelial-mesenchymal transition through the PKC/claudin-1-mediated signaling in human breast cancer cells [45]. Previous studies have shown deregulated expression of STC2 in a variety of cancers, with its expression correlating with poor prognosis [45][46][47][48][49][50][51].…”

Section: Discussionmentioning

confidence: 99%

Secretome profiling of oral squamous cell carcinoma-associated fibroblasts reveals organization and disassembly of extracellular matrix and collagen metabolic process signatures

et al. 2016

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An important role has been attributed to cancerassociated fibroblasts (CAFs) in the tumorigenesis of oral squamous cell carcinoma (OSCC), the most common tumor of the oral cavity. Previous studies demonstrated that CAFsecreted molecules promote the proliferation and invasion of OSCC cells, inducing a more aggressive phenotype. In this study, we searched for differences in the secretome of CAFs and normal oral fibroblasts (NOF) using mass spectrometrybased proteomics and biological network analysis. Comparison of the secretome profiles revealed that upregulated proteins involved mainly in extracellular matrix organization and disassembly and collagen metabolism. Among the upregulated proteins were fibronectin type III domain-containing 1 (FNDC1), serpin peptidase inhibitor type 1 (SERPINE1), and stanniocalcin 2 (STC2), the upregulation of which was validated by quantitative PCR and ELISA in an independent set of CAF cell lines. The transition of transforming growth factor beta 1 (TGF-β1)-mediating NOFs into CAFs was accompanied by significant upregulation of FNDC1, SERPINE1, and STC2, confirming the participation of these proteins in the CAF-derived secretome. Type I collagen, the main constituent of the connective tissue, was also associated with several upregulated biological processes. The immunoexpression of type I collagen N-terminal propeptide (PINP) was significantly correlated in vivo with CAFs in the tumor front and was associated with significantly shortened survival of OSCC patients. Presence of CAFs in the tumor stroma was also an independent prognostic factor for OSCC disease-free survival. These results demonstrate the value of secretome profiling for evaluating the role of CAFs in the tumor microenvironment and identify potential novel therapeutic targets such as FNDC1, SERPINE1, and STC2. Furthermore, type I collagen expression by CAFs, represented by PINP levels, may be a prognostic marker of OSCC outcome.Electronic supplementary material The online version of this article

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“…The protein concentrations of the lysates were measured with a Bio-Rad protein assay kit (Hercules, CA). Immunoblot analyses were performed as previously described [37, 38]. β-Actin antibodies were obtained from Santa Cruz Biotechnology.…”

Section: Methodsmentioning

confidence: 99%

“…Tumor inoculation assays in nude mice have been described previously [37–38]. Briefly, a total of 4 × 10 6 −1 × 10 7 231 PCDH cells or 231 PCDH HER2 cells suspended in 100 μl of sterile phosphate-buffered saline (PBS) were injected subcutaneously into the right hind legs of 24 male BALB/c athymic mice.…”

Section: Methodsmentioning

confidence: 99%

HER2 reduces breast cancer radiosensitivity by activating focal adhesion kinase in vitro and in vivo

et al. 2016

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Growing evidence has demonstrated that human epidermal growth factor receptor 2 (HER2) is involved in the radiation response to breast cancer. However, the underlying mechanism remains elusive. Therefore, we investigated if HER2 overexpression is associated with radiosensitivity of breast cancer. We constructed breast cancer cell lines differing in HER2 expression by transducing HER2 cDNA or short hairpin RNA against HER2. We then assessed the radiosensitivity and investigated the potential mechanism by using cell proliferation assay, cell adhesion assays, anoikis assays, colony formation assays, and western blotting analyses. We found that HER2 introduction in breast cancer cell lines MCF-7 (low HER2 expression) and MDA-MB-231 (HER2 is not expressed) promoted cell proliferation and invasion and enhanced cell adhesion and resistance to anoikis. Moreover, HER2 reduced radiosensitivity in these two cells compared with the corresponding control. The opposite results were observed when HER2 was silenced in breast cancer cell lines ZR-7530 and SK-BR-3 (both cells with high expression of HER2) using HER2 shRNA. In addition, animal experiment results showed HER2 could enhance the radioresistance of xenograft tumors. Further studies showed HER2 promoted the phosphorylation of focal adhesion kinase (Fak) and thereby up-regulated the expression of proteins associated with the epithelial-to-mesenchymal transition such as Claudin-1, ZO-1, and ZEB-1. The inhibition of Fak activity using the Fak inhibitor (PF-562281) restored the radiosensitivity in HER2-overexpressing cells. In conclusion, HER2 reduces the radiosensitivity of breast cancer by activating Fak in vitro and in vivo. Fak might be a potential target for the radiosensitization of HER2-overexpressed breast cancer.

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Stanniocalicin 2 Suppresses Breast Cancer Cell Migration and Invasion via the PKC/Claudin-1-Mediated Signaling

Cited by 52 publications

References 40 publications

STC2 promotes head and neck squamous cell carcinoma metastasis through modulating the PI3K/AKT/Snail signaling

STC2 promotes head and neck squamous cell carcinoma metastasis through modulating the PI3K/AKT/Snail signaling

Secretome profiling of oral squamous cell carcinoma-associated fibroblasts reveals organization and disassembly of extracellular matrix and collagen metabolic process signatures

HER2 reduces breast cancer radiosensitivity by activating focal adhesion kinase in vitro and in vivo

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