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

Our plain-English summary of The bone morphogenetic protein antagonist Gremlin is overexpressed in human malignant mesothelioma, by D.J. Wang, X.Y. Zhi, S.C. Zhang, et al (Oncology Reports, 2012).

The study

• Authors: D.J. Wang, X.Y. Zhi, S.C. Zhang, M. Jiang, P. Liu, X.P. Han, J. Li, Z. Chen, C.L. Wang
• Journal: Oncology Reports
• Published: 2012;27(1):58-64
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

This laboratory study looked at whether a gene called Gremlin is more active in malignant mesothelioma. Gremlin blocks a group of signalling proteins called bone morphogenetic proteins. The study did not measure asbestos exposure. The authors compared mesothelioma tissue removed during surgery with matched normal pleural tissue from the same patients. Gremlin messenger RNA was up-regulated in 7 of 8 tumor samples, and Gremlin protein was up-regulated in the same 7. In 20 more tumor samples, 85% (17 of 20) showed up-regulated Gremlin messenger RNA. Of six mesothelioma cell lines grown in the laboratory, four showed high Gremlin expression and two showed little or none. The gene's control region (its promoter) was active in the four and showed no activity in the two. When the authors reduced Gremlin in two cell lines using a technique called shRNA, the cells multiplied significantly less. The authors concluded that Gremlin seems to be a candidate cancer-promoting protein in mesothelioma and could be a target for diagnosis and treatment. They said studies with more tissue samples are needed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of gene expression in human malignant mesothelioma tissue samples and cell lines, including promoter-activity tests and gene knock-down experiments in cultured cells
• Who was studied: Malignant mesothelioma tissue and adjacent normal tissue taken at surgery from patients at local hospitals: 8 tumor samples paired with matched normal pleural tissue, plus 20 additional tumor samples. Also six human mesothelioma cell lines (H290, H2450, H28, H2052, MS-1 and REN).
• Exposure: No asbestos exposure was studied. The study measured expression of the Gremlin gene. In cell experiments, Gremlin expression was reduced using shRNA, with a scrambled shRNA as the control.
• Main results:
  • In the 8 tumor samples compared with paired normal tissue from the same patients, Gremlin messenger RNA was significantly up-regulated in 7 of 8.
  • Gremlin protein was also up-regulated in the same 7 of the 8 tumor samples, compared with their paired normal tissues.
  • In 20 additional tumor samples, 85% (17/20) showed up-regulated Gremlin messenger RNA (P<0.05).
  • Of 6 mesothelioma cell lines, 4 showed high Gremlin messenger RNA expression; little or no expression was found in H28 and MS-1.
  • The Gremlin promoter construct showed significantly high activity (P<0.04) in the 4 cell lines that strongly expressed Gremlin, and no activity in MS-1 and H28.
  • Reducing Gremlin with shRNA in cell lines H290 and H2450 led to significant suppression of cell proliferation in both lines (P<0.002).
• The authors' conclusion: The authors concluded that Gremlin seems to be a candidate oncoprotein (cancer-promoting protein) in the development of human malignant mesothelioma and could be a target for developing diagnostic and treatment strategies.
• Limitations the authors state:
  • The authors stated that further investigation with a larger number of mesothelioma tissue samples is needed.
  • The authors stated that further studies are needed on Gremlin's cellular functions and regulatory mechanisms, including its interaction with BMP family members and downstream signalling.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Tumorigenesis.

Related studies

• Gremlin-mediated decrease in bone morphogenetic protein signaling promotes pulmonary fibrosis — M. Myllärniemi, P. Lindholm, et al. (2008)
• DNA methylation status of REIC/Dkk-3 gene in human malignancies — T. Hayashi, H. Asano, et al. (2012)
• TRAIL and proteasome inhibitors combination induces a robust apoptosis in human malignant pleural mesothelioma cells through Mcl-1 and Akt protein cleavages — B.Z. Yuan, J. Chapman, et al. (2013)
• Activated cAMP response element binding protein is overexpressed in human mesotheliomas and inhibits apoptosis — A. Shukla, M.W. Bosenberg, et al. (2009)
• Soluble ICAM-1, MCP-1, and MIP-2 protein secretion by rat pleural mesothelial cells following exposure to amosite asbestos — G.D. Hill, J.B. Mangum, et al. (2003)
• Expression of Gab1 lacking the pleckstrin homology domain is associated with neoplastic progression — H. Kameda, J.I. Risinger, et al. (2001)

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