Anterior gradient protein 2 expression in high grade head and neck squamous cell carcinoma correlated with cancer stem cell and epithelial mesenchymal transition

Ma, Si‐Rui; Wang, Weiming; Huang, Cong-Fa; Zhang, Wenfeng; Sun, Zhi‐Jun

doi:10.18632/oncotarget.3556

Cited by 47 publications

(61 citation statements)

References 52 publications

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“…CD44, KLF4, ALDH1 and SOX2). Our previous data have proven that C4.4A and AGR2 were activated in SCCHN and associated with EMT or cancer stem cell . In this study, both C4.4A and AGR2 have a strong correlation and a similar expression pattern with TRAF6.…”

Section: Discussionsupporting

confidence: 64%

“…5B). In addition, our previous data have proved that C4.4A and AGR2 were activated in SCCHN and associated with EMT or CSCs [39,44]; moreover, both of them have a strong correlation and a similar expression pattern with TRAF6 (C4.4A, P < 0.01, r = 0.3694; AGR2, P < 0.001, r = 0.4107; Fig. 5B and C).…”

Section: Traf6 Was Correlated With Emt and Cscs In Mice And Human Scchnmentioning

confidence: 61%

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TRAF6 regulates tumour metastasis through EMT and CSC phenotypes in head and neck squamous cell carcinoma

Chen

et al. 2017

J Cellular Molecular Medi

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Epithelial–mesenchymal transition (EMT) is associated with metastasis formation, generation and maintenance of cancer stem cells (CSCs). However, the regulatory mechanisms of CSCs have not been clarified. This study aims to investigate the role of TNF receptor‐associated factor 6 (TRAF6) on EMT and CSC regulation in squamous cell carcinoma of head and neck (SCCHN). We found TRAF6 was overexpressed in human SCCHN tissues, and high TRAF6 expression was associated with lymphatic metastasis and resulted in poor prognosis in patients with SCCHN. In addition, elevated TRAF6 expression was observed in several HNSCC cell lines, and wound healing and transwell assay results showed that TRAF6 knockdown inhibited the migration and invasion ability of the SCCHN cells. Moreover, the expression of Vimentin, Slug and N‐cadherin was down‐regulated and that of E‐cadherin was elevated after TRAF6 knockdown but decreased by transforming growth factor beta 1 (TGF‐β1) and CAL27 similar to mesenchymal cells formed after TGF‐β1 induction. In addition, the expression levels of CD44, ALDH1, KLF4 and SOX2 were inhibited after TRAF6 knockdown, and the anchor‐dependent colony formation number and sphere number were remarkably reduced. Flow cytometry showed TRAF6 knockdown reduced ALDH1‐positive cancer stem cells. We also demonstrated that TRAF6 is closely associated with EMT process and cancer stem cells using a Tgfbr1/Pten 2cKO mice SCCHN model and human SCCHN tissue microarray. Our findings indicate that TRAF6 plays a role in EMT phenotypes, the generation and maintenance of CSCs in SCCHN, suggesting that TRAF6 is a potential therapeutic target for SCCHN.

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Section: Discussionsupporting

confidence: 64%

Section: Traf6 Was Correlated With Emt and Cscs In Mice And Human Scchnmentioning

confidence: 61%

TRAF6 regulates tumour metastasis through EMT and CSC phenotypes in head and neck squamous cell carcinoma

Chen

et al. 2017

J Cellular Molecular Medi

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“…31 Here, we revealed that AGR2 is also overexpressed at the protein level in pancreatic CSC compared with non-stem cancer cells. Taken together, our data indicate that AGR2 plays an important role in PDAC initiation and development, potentially by regulating the maintenance of stemness and progenitor cell differentiation.…”

Section: Discussionmentioning

confidence: 76%

ER stress protein AGR2 precedes and is involved in the regulation of pancreatic cancer initiation

et al. 2016

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The mechanisms of initiation of pancreatic ductal adenocarcinoma (PDAC) are still largely unknown. In the present study, we analysed the role of anterior gradient-2 (AGR2) in the earliest stages of pancreatic neoplasia. Immunohistochemical analysis of chronic pancreatitis (CP) and peritumoral areas in PDAC tissues showed that AGR2 was present in tubular complexes (TC) and early pancreatic intraepithelial neoplasia (PanINs). Moreover, AGR2 was also found in discrete subpopulations of non-transformed cells neighbouring these pre-neoplastic lesions. In primary cells derived from human patient-derived xenograft (PDX) model, flow-cytometry revealed that AGR2 was overexpressed in pancreatic cancer stem cells (CSC) compared with non-stem cancer cells. In LSL-KrasG12D;Pdx1-Cre (KC) mouse model Agr2 induction preceded the formation of pre-neoplastic lesions and their development was largely inhibited by Agr2 deletion in engineered LSL-KrasG12D;Pdx1-Cre; Agr2−/− mice. In vitro, AGR2 expression was stimulated by tunicamycin-induced endoplasmic reticulum (ER) stress in both KRAS wild-type normal pancreas cells, as well as in KRAS mutated pancreatic cancer cells and was essential for ER homoeostasis. The unfolded protein response proteins GRP78, ATF6 and XBP1s were found expressed in CP and PDAC peritumoral tissues, but in contrast to AGR2, their expression was switched off during TC and PanIN formation. Real-time PCR and ELISA analyses showed that ER stress induced a pro-inflammatory phenotype in pancreatic normal, cancer and stellate cells. Moreover, AGR2 expression was inducible by paracrine transfer of ER stress and pro-inflammation between different pancreatic cell types. Our findings demonstrate that AGR2 induced in ER-stressed and inflammatory pre-neoplastic pancreas is a potential marker of cancer progenitor cells with an important functional role in PDAC initiation.

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“…c), suggesting that FOXA1 may not affect the generation of CSCs. The colony formation assay is widely used to evaluate the proliferative ability of immature cells . As shown in Figure (d,e), the number of colonies derived from shFOXA1 MCF‐7 cells significantly decreased compared to control cells.…”

Section: Resultsmentioning

confidence: 96%

“…The colony formation assay is widely used to evaluate the proliferative ability of immature cells. (28,46) As shown in Figure 5(d,e), the number of colonies derived from shFOXA1 MCF-7 cells significantly decreased compared to control cells. Taken together, these findings indicate that FOXA1 appears to work as a factor in the proliferation rather than maintenance of stemness-related genes or the activation of CSCs.…”

Section: Ectopic Foxa1 Expression In Mammospheres Is Correlated To 4-mentioning

confidence: 85%

FOXA1 expression affects the proliferation activity of luminal breast cancer stem cell populations

et al. 2016

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The expression of estrogen receptor is the key in most breast cancers (BC) and binding of estrogen receptor to the genome correlates to Forkhead protein (FOXA1) expression. We herein assessed the correlation between the cancer stem cell (CSC) population and FOXA1 expression in luminal BC. We established luminal BC cells derived from metastatic pleural effusion and analyzed the potency of CSC and related factors with established luminal BC cell lines. We also confirmed that mammosphere cultures have an increased aldehyde dehydrogenase‐positive population, which is one of the CSC markers, compared with adherent culture cells. Using a quantitative PCR analysis, we found that mammosphere forming cells showed a higher expression of FOXA1 and stemness‐related genes compared with adherent culture cells. Furthermore, the growth activity and colony‐forming activity of 4‐hydroxytamoxifen‐treated BC cells were inhibited in a mammosphere assay. Interestingly, 4‐hydroxytamoxifen‐resistant cells had significantly increased FOXA1 gene expression levels. Finally, we established short hairpin RNA of FOXA1 (shFOXA1) MCF‐7 cells and investigated the relationship between self‐renewal potential and FOXA1 expression. As a result, we found no significant difference in the number of mammospheres but decreased colony formation in shFOXA1 MCF‐7 cells compared with control. These results suggest that the expression of FOXA1 appears to be involved in the proliferation of immature BC cells rather than the induction of stemness‐related genes and self‐renewal potency of CSCs.

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Anterior gradient protein 2 expression in high grade head and neck squamous cell carcinoma correlated with cancer stem cell and epithelial mesenchymal transition

Cited by 47 publications

References 52 publications

TRAF6 regulates tumour metastasis through EMT and CSC phenotypes in head and neck squamous cell carcinoma

TRAF6 regulates tumour metastasis through EMT and CSC phenotypes in head and neck squamous cell carcinoma

ER stress protein AGR2 precedes and is involved in the regulation of pancreatic cancer initiation

FOXA1 expression affects the proliferation activity of luminal breast cancer stem cell populations

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