The bone morphogenetic protein antagonist Gremlin is overexpressed in human malignant mesothelioma

Abstract

Abstract.Gremlin is a member of the bone morphogenetic protein (BMP) antagonist family and its antagonistic effect is likely through direct binding to BMP proteins. As an antagonist of BMP, Gremlin plays a role in regulating organogenesis, body patterning and tissue differentiation. Recent studies have shown a deregulation of Gremlin in several types of human cancers. However, the role of Gremlin in human malignant mesothelioma (MM) is still unknown. In this study, we investigated the expression of Gremlin in human MM. We found that Gremlin mRNA and protein were both overexpressed in the majority of primary MM tissue samples that we examined. We also observed high level expression of the Gremlin gene in 4 of the 6 MM cell lines. Consistently, we found that the Gremlin promoter activity was significantly elevated in those MM cell lines expressing the Gremlin gene. On the other hand, no activity of the Gremlin promoter was detected in the two MM cell lines lacking Gremlin expression. Moreover, to examine the functional significance of the Gremlin overexpression in MM, we used shRNA to knock down Gremlin expression in MM cell lines expressing Gremlin and found that inhibition of Gremlin expression significantly suppressed proliferation of those MM cells. Taken together, our results suggest that the BMP antagonist Gremlin is overexpressed in MM and that aberrant activation of Gremlin may play a critical role in the tumorigenesis of human MM.

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).…”

GREM1 is expressed in the cancer-associated myofibroblasts of basal cell carcinomas

“…As mentioned earlier, stromal GREM1 expression has been demonstrated not only in BCCs but also in many invasive carcinomas, such as carcinomas of the esophagus, pancreas, colon, lung, breast, and mesotheliomas [7, 21]. This suggests that GREM1 -expressing fibroblasts are essential components of the cancer microenvironment.…”

Implications of human genome structural heterogeneity: functionally related genes tend to reside in organizationally similar genomic regions

“…Cluster H1-i also included genes that have additional roles in the epithelium as well as in differentiation and maturation of other tissues (see Figure 1 , Additional file 3 ). Some examples of these include: SPRR4 , induced by ultraviolet light and other environmental stresses [ 35 ]; NOTCH2 , known to delay hepatoblast maturation during early hepatic organogenesis, and JAG1 playing a role in hematopoiesis [ 36 ]; GREM1 , which is involved in regulating organogenesis, body patterning, and tissue differentiation [ 37 ]; ONECUT1, which encodes a transcription factor mediating complex processes in the liver and pancreas related to cell proliferation, cell-cycle regulation, cell differentiation, and organogenesis [ 38 ], and AGT , reported to be involved in the epithelial-to-mesenchymal transition in renal epithelial cells [ 39 ] and in maintaining blood pressure [ 40 ] (see Additional file 3 ).…”