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The functional role of INSL3 and its receptor RXFP2 in carcinogenesis is largely unknown. We have previously demonstrated (pro-)cathepsin-L as a target of INSL3 in human thyroid cancer cells facilitating penetration of tumor cells through elastin matrices. We demonstrate the expression of RXFP2 in human thyroid tissues and in mouse follicular thyroid epithelial cells using Cre-recombinase transgene driven by Rxfp2 promoter. Recombinant and secreted INSL3 increased the motility of thyroid carcinoma (TC) cells in an autocrine/paracrine manner. This effect required the presence of RXFP2. We identified S100A4 as a novel INSL3 target molecule and showed that S100A4 facilitated INSL3-induced enhanced motility. Stable transfectants of the human follicular TC cell line FTC-133 expressing and secreting bioactive human INSL3 displayed enhanced anchorageindependent growth in soft agar assays. Xenotransplant experiments in nude mice showed that INSL3, but not EGFP-mock transfectants, developed fast-growing and highly vascularized xenografts. We used human umbilical vein endothelial cells in capillary tube formation assays to demonstrate increased 2-dimensional tube formations induced by recombinant human INSL3 and human S100A4 comparable to the effect of vascular endothelial growth factor used as positive control. We conclude that INSL3 is a powerful and multifunctional promoter of tumor growth and angiogenesis in human thyroid cancer cell xenografts. INSL3 actions involve RXFP2 activation and the secretion of S100A4 and (pro-)cathepsin-L.Comprising 1% of all malignancies, thyroid cancer is the most common carcinoma of endocrine glands and displays the highest increase in incidence of all malignancies in the United States over the time interval 1975-2000 (http://seer. cancer.gov/csr/1975_2004/; www.cancer.ca). 1 There are 4 types of thyroid carcinoma (TC) that comprise >98% of all thyroid malignancies: papillary (PTC), follicular (FTC), anaplastic, undifferentiated (UTC) and medullary TC (MTC). We showed previously that the insulin-like peptide hormone, insulin-like peptide 3 (INSL3) and a novel INSL3 splice form are present in human hyperplastic thyroid adenoma and thyroid cancer. 2 INSL3 is a member of the relaxin family and signals through the type C leucine-rich repeat G proteincoupled receptor RXFP2, also named GREAT and LGR8. [3][4][5][6][7] Activation of RXFP2 causes an increase in cAMP levels and, via the actions of the small G-proteins Ga s and Ga oB , activates and negatively modulates adenylate cyclase activity, respectively, which affects cAMP-response element transcriptional activity. [8][9][10] Deletion of the gene for INSL3 or the INSL3 receptor causes impaired transabdominal testis descent and cryptorchidism in rodents and boys. [11][12][13][14] Both INSL3 and the homologous peptide relaxin are found in tumor tissues but little information is currently available on the functional role of both the INSL3-RXFP2 and the relaxin-RXFP1 system in cancer cells. 15 In prostate cancer, increasing evidence from cell an...
The functional role of INSL3 and its receptor RXFP2 in carcinogenesis is largely unknown. We have previously demonstrated (pro-)cathepsin-L as a target of INSL3 in human thyroid cancer cells facilitating penetration of tumor cells through elastin matrices. We demonstrate the expression of RXFP2 in human thyroid tissues and in mouse follicular thyroid epithelial cells using Cre-recombinase transgene driven by Rxfp2 promoter. Recombinant and secreted INSL3 increased the motility of thyroid carcinoma (TC) cells in an autocrine/paracrine manner. This effect required the presence of RXFP2. We identified S100A4 as a novel INSL3 target molecule and showed that S100A4 facilitated INSL3-induced enhanced motility. Stable transfectants of the human follicular TC cell line FTC-133 expressing and secreting bioactive human INSL3 displayed enhanced anchorageindependent growth in soft agar assays. Xenotransplant experiments in nude mice showed that INSL3, but not EGFP-mock transfectants, developed fast-growing and highly vascularized xenografts. We used human umbilical vein endothelial cells in capillary tube formation assays to demonstrate increased 2-dimensional tube formations induced by recombinant human INSL3 and human S100A4 comparable to the effect of vascular endothelial growth factor used as positive control. We conclude that INSL3 is a powerful and multifunctional promoter of tumor growth and angiogenesis in human thyroid cancer cell xenografts. INSL3 actions involve RXFP2 activation and the secretion of S100A4 and (pro-)cathepsin-L.Comprising 1% of all malignancies, thyroid cancer is the most common carcinoma of endocrine glands and displays the highest increase in incidence of all malignancies in the United States over the time interval 1975-2000 (http://seer. cancer.gov/csr/1975_2004/; www.cancer.ca). 1 There are 4 types of thyroid carcinoma (TC) that comprise >98% of all thyroid malignancies: papillary (PTC), follicular (FTC), anaplastic, undifferentiated (UTC) and medullary TC (MTC). We showed previously that the insulin-like peptide hormone, insulin-like peptide 3 (INSL3) and a novel INSL3 splice form are present in human hyperplastic thyroid adenoma and thyroid cancer. 2 INSL3 is a member of the relaxin family and signals through the type C leucine-rich repeat G proteincoupled receptor RXFP2, also named GREAT and LGR8. [3][4][5][6][7] Activation of RXFP2 causes an increase in cAMP levels and, via the actions of the small G-proteins Ga s and Ga oB , activates and negatively modulates adenylate cyclase activity, respectively, which affects cAMP-response element transcriptional activity. [8][9][10] Deletion of the gene for INSL3 or the INSL3 receptor causes impaired transabdominal testis descent and cryptorchidism in rodents and boys. [11][12][13][14] Both INSL3 and the homologous peptide relaxin are found in tumor tissues but little information is currently available on the functional role of both the INSL3-RXFP2 and the relaxin-RXFP1 system in cancer cells. 15 In prostate cancer, increasing evidence from cell an...
Objective. This study aimed to screen prognostic gene signature of glioblastoma (GBM) to construct prognostic model. Methods. Based on the GBM information in the Cancer Genome Atlas (TCGA, training set), prognostic genes (Set X) were screened by Cox regression. Then, the optimized prognostic gene signature (Set Y) was further screened by the Cox-Proportional Hazards (Cox-PH). Next, two prognostic models were constructed: model A was based on the Set Y; model B was based on part of the Set X. The samples were divided into low- and high-risk groups according to the median prognosis index (PI). GBM datasets in Gene Expression Ominous (GEO, GSE13041) and Chinese Glioma Genome Atlas (CGGA) were used as the testing datasets to confirm the prognostic models constructed based on TCGA. Results. We identified that the prognostic 14-gene signature was significantly associated with the overall survival (OS) in the TCGA. In model A, patients in high- and low-risk groups showed the significantly different OS (P = 7.47 × 10−9, area under curve (AUC) 0.995) and the prognostic ability were also confirmed in testing sets (P=0.0098 and 0.037). The model B in training set was significant but failed in testing sets. Conclusion. The prognostic model which was constructed based on the prognostic 14-gene signature presented a high predictive ability for GBM. The 14-gene signature may have clinical implications in the subclassification of GBM.
Background. Oral squamous cell carcinoma (OSCC) is a commonly encountered head and neck malignancy. Increasing evidence shows that there are abnormal immune response and chronic cell hypoxia in the development of OSCC. However, there is a lack of a reliable hypoxia-immune-based gene signature that may serve to accurately prognosticate OSCC. Methods. The mRNA expression data of OSCC patients were extracted from the TCGA and GEO databases. Hypoxia status was identified using the t-distributed Stochastic Neighbor Embedding (t-SNE) algorithm. Both ESTIMATE and single-sample gene-set enrichment analysis (ssGSEA) were used for further evaluation of immune status. The DEGs in different hypoxia and immune status were determined, and univariate Cox regression was used to identify significantly prognostic genes. A machine learning method, least absolute shrinkage and selection operator (LASSO) Cox regression analysis, allowed us to construct prognostic gene signature to predict the overall survival (OS) of OSCC patients. Results. A total of 773 DEGs were identified between hypoxia high and low groups. According to immune cell infiltration, patients were divided into immune high, medium, and low groups and immune-associated DEGs were identified. A total of 193 overlapped DEGs in both immune and hypoxia status were identified. With the univariate and LASSO Cox regression model, eight signature mRNAs (FAM122C, RNF157, RANBP17, SOWAHA, KIAA1211, RIPPLY2, INSL3, and DNAH1) were selected for further calculation of their respective risk scores. The risk score showed a significant association with age and perineural and lymphovascular invasion. In the GEO validation cohort, a better OS was observed in patients from the low-risk group in comparison with those in the high-risk group. High-risk patients also demonstrated different immune infiltration characteristics from the low-risk group and the low-risk group showed potentially better immunotherapy efficacy in contrast to high-risk ones. Conclusion. The hypoxia-immune-based gene signature has prognostic potential in OSCC.
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