A 25 kDa protein, it carries a carboxy-terminal cysteine-rich motif that is homologous with a protein domain shared by members of secreted CHIR-99021 proteins such as DAN and Cerberus. Drm was identified as a novel gene that is suppressed in cells transformed by v-ras, v-src, v-raf, and v-fos. It was shown that DRM can inhibit the growth of normal but not transformed cells in culture. A possible tumor-suppressor role was proposed for drm on the basis of its down-regulation in these transformed cell lines and it was hypothesized that high levels of drm inhibit the growth or viability of normal cells, but that transformed cells are resistant to this inhibitory effect. Studies of normal development of the limb have implicated a role for Gremlin in proper establishment of limb bud morphology. Gremlin indirectly enhances FGF-mediated limb outgrowth while simultaneously inhibiting chondrogenesis and cell death. Sonic Hedgehog has also been shown to upregulate and maintain Gremlin expression, enabling Gremlin to relieve the repressive effects of BMP-4 on FGF-4 expression, yielding a net positive feedback to increase SHH. The importance of the interaction between Gremlin and the BMP signaling pathway in the normal development of the proximal-distal patterning of the lung has previously been investigated. Gremlin acts as a functional physiological antagonist that restricts BMP-4 activity to the distal bud, thereby regulating the number of branching epithelial sacs. Similarly, antagonism of BMP-4 signal using the BMP antagonist Xnoggin results in a severe reduction in distal epithelial cell types and an increase in proximal cell types. Overexpression of Gremlin in the distal lung epithelium using an SP-C promoter in mice results in transgenic lungs that phenotypically resemble proximal airways epithelium with decreased squamous epithelium. Deletion of GREM1 in mouse embryonic stem cells results in a neonatal lethal phenotype characterized by a reduction in differentiated alveoli and multi-layered epithelium in comparison to wild-type embryos. RNA and protein analysis indicates that Gremlin is frequently undetectable in multiple malignant cell lines, including neuroblastoma, glioblastoma, medulloblastoma, and colon adenocarcinoma. The pattern of expression suggests a possible role as an inhibitor of tumor progression in these lineages. Overexpression of Gremlin was sufficient to inhibit the neoplastic phenotype of both Daoy and Soas-2 cell line. Analysis of publicly-available microarray data also suggests a significant downregulation of Gremlin in tumors of the CNS. While these studies have suggested a possible tumor-suppressive role for Gremlin, recent work has shown an oncogenic role for Gremlin in other tumor types. Gremlin is over-expressed in stromal cells associated with basal cell carcinomas of the skin, and can promote cell proliferation in this model. Gremlin is also upregulated in the lung cancer cell line A549 per a semiquantitative northern blot analysis. It was recently reported that Gremlin is overexpressed in many malignant mesothelioma tissue specimens. Inhibition of Gremlin via shRNA significantly inhibited proliferation of MM cell lines. The function of Gremlin in cancer cells is controversial and appears to work in a tissue-specific manner. In lung cancer, nothing to date is known about the role of Gremlin. Thus, we performed genetic and histological analysis of Gremlin in a large number of lung AD and squamous cell carcinoma samples. mRNA and protein expression analysis of Gremlin were done in 161 matched tumor-normal pairs. Of these, 96 pairs were of AD, while 65 of the pairs were from SCC.