The bone morphogenetic protein antagonist gremlin 1 is overexpressed in human cancers and interacts with YWHAH protein

Abstract

BackgroundBasic studies of oncogenesis have demonstrated that either the elevated production of particular oncogene proteins or the occurrence of qualitative abnormalities in oncogenes can contribute to neoplastic cellular transformation. The purpose of our study was to identify an unique gene that shows cancer-associated expression, and characterizes its function related to human carcinogenesis.MethodsWe used the differential display (DD) RT-PCR method using normal cervical, cervical cancer, metastatic cervical tissues, and cervical cancer cell lines to identify genes overexpressed in cervical cancers and identified gremlin 1 which was overexpressed in cervical cancers. We determined expression levels of gremlin 1 using Northern blot analysis and immunohistochemical study in various types of human normal and cancer tissues. To understand the tumorigenesis pathway of identified gremlin 1 protein, we performed a yeast two-hybrid screen, GST pull down assay, and immunoprecipitation to identify gremlin 1 interacting proteins.ResultsDDRT-PCR analysis revealed that gremlin 1 was overexpressed in uterine cervical cancer. We also identified a human gremlin 1 that was overexpressed in various human tumors including carcinomas of the lung, ovary, kidney, breast, colon, pancreas, and sarcoma. PIG-2-transfected HEK 293 cells exhibited growth stimulation and increased telomerase activity. Gremlin 1 interacted with homo sapiens tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, eta polypeptide (14-3-3 eta; YWHAH). YWHAH protein binding site for gremlin 1 was located between residues 61–80 and gremlin 1 binding site for YWHAH was found to be located between residues 1 to 67.ConclusionGremlin 1 may play an oncogenic role especially in carcinomas of the uterine cervix, lung, ovary, kidney, breast, colon, pancreas, and sarcoma. Over-expressed gremlin 1 functions by interaction with YWHAH. Therefore, Gremlin 1 and its binding protein YWHAH could be good targets for developing diagnostic and therapeutic strategies against human cancers.

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

“…Similar findings have been suggested for side population (SP) cells in endometrial cancer and ALDH1-positive cells in cervical cancer (31)(32)(33)(34)(35)(36). Gremlin 1 is also reported to be expressed in cervical cancer compared to normal tissues of the cervix (37). A few studies have investigated the significance of BMPs in cervical cancer (38)(39)(40), however, there are no studies on the clinicopathological significance of Gremlin 1 in cervical cancer nor on the function of Gremlin 1 in CSC-like cells of cervical cancer.…”

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

“…As an antagonist of BMP proteins likely through direct binding to BMP proteins (6), Gremlin has recently been shown to be deregulated during tumorigenesis of several types of cancers such as lung, breast, ovarian and cervical cancers (20)(21)(22)(23)(24)(25). However, the role of Gremlin in malignant mesothelioma has not been studied before and still remains unknown.…”

“…Inactivation of the BMP genes has been reported in several cancer types, including lung, breast, prostate and colon cancers, lymphomas and mesotheliomas (9)(10)(11)(12)(13)(14)(15), suggesting the importance of BMPs in tumorigenesis of these cancers. As an antagonist of BMP proteins, Gremlin also plays important roles during early development (16)(17)(18)(19), as well as tumorigenesis of several types of cancers (20)(21)(22)(23)(24)(25). However, the role of Gremlin in ΜΜ has not been reported before and still remains unknown.…”

Systems analysis of the prostate tumor suppressor NKX3.1 supports roles in DNA repair and luminal cell differentiation

“…Many of the most downregulated genes were previously shown to be overexpressed in prostate and other cancers ( Supplementary Table 2). This applies, for example, to eukaryotic translation elongation factor 1 alpha (EEF1A2) which is a potential oncogene 66 , the BMP antagonist gremlin 1 67 , and the transcription factor FOXD1 68 . N-cadherin, which is frequently found to replace epithelial cadherin forms in prostate cancers (“cadherin switch”) was also strongly downregulated 69 .…”