Gremlin is Overexpressed in Lung Adenocarcinoma and Increases Cell Growth and Proliferation in Normal Lung Cells

Abstract

BackgroundGremlin, a member of the Dan family of BMP antagonists, is a glycosylated extracellular protein. Previously Gremlin has been shown to play a role in dorsal-ventral patterning, in tissue remodeling, and recently in angiogenesis. Evidence has previously been presented showing both over- and under-expression of Gremlin in different tumor tissues. Here, we sought to quantify expression of Gremlin in cancers of the lung and performed in vitro experiments to check whether Gremlin promotes cell growth and proliferation.Methodology/Principal FindingsExpression of Gremlin in 161 matched tumor and normal lung cancer specimens is quantified by quantitative real-time PCR and protein level is measured by immunohistochemistry. GREM1 was transfected into lung fibroblast and epithelial cell lines to assess the impact of overexpression of Gremlin in vitro.ResultsLung adenocarcinoma but not squamous cell carcinoma shows a significant increase in Gremlin expression by mRNA and protein level. Lung fibroblast and epithelial cell lines transfected with GREM1 show significantly increased cell proliferation.Conclusions/SignificanceOur data suggest that Gremlin acts in an oncogenic manner in lung adenocarcinoma and could hold promise as a new diagnostic marker or potential therapeutic target in lung AD or general thoracic malignancies.

Investigation of GREMLIN 1, COL15A1 immunoreactivity and the relationship between microvessel density and GREMLIN 1 in papillary renal cell carcinoma and chromophobe renal cell carcinoma

“…Recent studies have demonstrated upregulation of GREM 1 in a variety of human cancers (12)(13)(14)(15). In the present study, GREM1 expression did not differ statistically significantly between tumor tissue and neighboring intact tissue in PRCC patients but tumor tissue showed significantly higher GREM1 expression in CRCC patients (p=0.006).…”

Glioma cancer stem cells secrete Gremlin1 to promote their maintenance within the tumor hierarchy

“…These antagonists share a common cysteine knot protein motif with BMPs and inhibit the ligands by direct binding and prevention of ligand-receptor interaction (Groppe et al 2002). Antagonists include Gremlin1, Noggin, Chordin, Ventroptin, and Brorin and play protumorigenic roles in a number of different cancer types (Namkoong et al 2006;Sneddon et al 2006;Hsu et al 2008;Secondini et al 2011;Gao et al 2012;Kim et al 2012;Mulvihill et al 2012). In examining the mRNA expression of several BMP antagonists in CSC and nonstem glioma cell populations, we found robust expression of Gremlin1 in the CSCs, with comparatively modest or absent expression of other antagonists ( Fig.…”

Clinical significance of Gremlin 1 in cervical cancer and its effects on cancer stem cell maintenance

“…However, these findings should not be interpreted to conclude that cases of poor prognosis have a larger population of CSCs. Gremlin 1 was found to be secreted from stromal cancer-associated fibroblast (CAFs) in colon cancer and its expression was localized to invasion fronts (24)(25)(26). On the other hand, Gremlin 1 was found to be secreted by CSCs in glioblastoma and was thought to prevent CSCs from differentiating by antagonizing the effects ofBMPs (27,28).…”

“…BMPs are members of the transforming growth factor (TGF)-β superfamily and play an essential role during development and differentiation while Gremlin 1 is also related to differentiation in combination with BMPs and its dysregulation results in developmental diseases (20)(21)(22)(23). Gremlin 1 is overexpressed in various types of human cancers (24)(25)(26). Recently several studies have demonstrated that CSCs prevent the BMP differentiating effect by secreting Gremlin 1 in glioblastoma, suggesting that Gremlin 1 plays a role in maintenance of CSC properties (27,28).…”