Dysregulated expression of MIC-1/PDF in human prostate tumor cells

Karan, Dev; Chen, Siu Ju; Johansson, Sonny L.; Singh, Ajay P.; Paralkar, Vishwas; Lin, Ming‐Fong; Batra, Surinder K.

doi:10.1016/s0006-291x(03)00823-4

Cited by 63 publications

(61 citation statements)

References 21 publications

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“…35 GDF15 has been reported by multiple studies to be a target of p53 in response to both DNA damage and p53 induction by Nutlin-3, [4][5][6]20,36,37 and these and other results have attributed growthinhibitory and tumor-suppressive functions to GDF15. [7][8][9][10][11]38,39 However, other studies have found elevated expression of GDF15 in many human cancers, 15,[40][41][42] and high levels of GDF15 expression correspond to increased metastasis in both mouse models and human patients. [16][17][18][19][20]41,43 Although it is possible that GDF15 exerts pleiotropic effects on the growth of cancer cells, prior studies may have conflated the function of GDF15 with that of the embedded miR-3189.…”

Section: Discussionmentioning

confidence: 99%

Growth differentiation factor-15 encodes a novel microRNA 3189 that functions as a potent regulator of cell death

Jones

Mahadevan

et al. 2015

Cell Death Differ

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According to the latest version of miRBase, approximately 30% of microRNAs (miRNAs) are unique to primates, but the physiological function of the vast majority remains unknown. In this study, we identified miR-3189 as a novel, p53-regulated, primate-specific miRNA embedded in the intron of the p53-target gene GDF15. Antagonizing miR-3189 increased proliferation and sensitized cells to DNA damage-induced apoptosis, suggesting a tumor suppressor function for endogenous miR-3189. Identification of genome-wide miR-3189 targets revealed that miR-3189 directly inhibits the expression of a large number of genes involved in cell cycle control and cell survival. In addition, miR-3189 downregulated the expression of multiple p53 inhibitors resulting in elevated p53 levels and upregulation of several p53 targets including p21 (CDKN1A), GADD45A and the miR-3189 host gene GDF15, suggesting miR-3189 auto-regulation. Surprisingly, miR-3189 overexpression in p53-/-cells upregulated a subset of p53-targets including GDF15, GADD45A, and NOXA, but not CDKN1A. Consistent with these results, overexpression of miR-3189 potently induced apoptosis and inhibited tumorigenicity in vivo in a p53-independent manner. Collectively, our study identified miR-3189 as a novel, primate-specific miRNA whose effects are mediated by both p53-dependent and p53-independent mechanisms. miR-3189 may, therefore, represent a novel tool that can be utilized therapeutically to induce a potent proapoptotic effect even in p53-deficient tumors.

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Section: Discussionmentioning

confidence: 99%

Growth differentiation factor-15 encodes a novel microRNA 3189 that functions as a potent regulator of cell death

Jones

Mahadevan

et al. 2015

Cell Death Differ

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“…43 A similar upregulation of GDF15 immunoreactivity was also reported in adenocarcinomas including colorectal, gastric, and prostate cancers. 30,34,44 Wang et al 42 also indicated that positive staining of GDF15 in ESCC tissues was mostly confined to the cytoplasm of ESCC cells with a diffuse pattern. In the present study too, the GDF15-positive cells in the ESCC tissues were mostly confined to the cytoplasm of ESCC cells, whereas GDF15 immunoreactions were detected in other stromal cells such as erythrocytes and macrophages.…”

Section: Gdf15 Increased the Growth Of The Escc Cell Lines By Triggermentioning

confidence: 98%

GDF15 derived from both tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression via Akt and Erk pathways

Urakawa

Utsunomiya

Nishio

et al. 2015

Laboratory Investigation

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Tumor-associated macrophages (TAMs) are known to be involved in the progression, angiogenesis, and motility of various cancers. We previously reported the association between an increased number of infiltrating TAMs with tumor progression and poor prognosis in esophageal squamous cell carcinomas (ESCCs). To study the roles of TAMs in ESCC, we first exposed peripheral blood monocyte (PBMo)-derived macrophages from healthy volunteers to conditioned media of TE series human ESCC cell line (TECM) and confirmed the induction of the expression of the M2 macrophage marker CD204 and the protumorigenic factors interleukin (IL)-10, VEGFA, and MMPs. Next, we compared gene expression profiles between PBModerived macrophages stimulated with or without TECM by cDNA microarray and focused on growth differentiation factor 15 (GDF15) among the highly expressed genes including IL-6, IL-8, and CXCL1. Our immunohistochemical study of 70 surgically resected ESCCs revealed that GDF15 was present not only in cancer cells but also in macrophages. The high expression of GDF15 in the ESCCs was significantly correlated with several more malignant phenotypes including vessel invasion, lymph node metastasis, and clinical stages. Patients with high GDF15 expression showed significantly poorer disease-free survival (P = 0.011) and overall survival (P = 0.041). We also found that recombinant human GDF15 promotes cell proliferation and the phosphorylation of both Akt and Erk1/2 in ESCC cell lines in vitro. These results indicate that GDF15 is secreted by both TAMs and cancer cells in the tumor microenvironment and is associated with aberrant growth and a poor prognosis in human ESCC.

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“…The tissue sections (CF and normal) were processed for IHC analysis as described previously (Karan et al, 2003).…”

Section: Immunohistochemistrymentioning

confidence: 99%

MUC4 expression is regulated by cystic fibrosis transmembrane conductance regulator in pancreatic adenocarcinoma cells via transcriptional and post-translational mechanisms

et al. 2006

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MUC4 mucin is a high molecular weight transmembrane glycoprotein that plays important roles in tumour biology. It is aberrantly expressed in pancreatic adenocarcinoma, while not being detectable in the normal pancreas. Previous studies have demonstrated that the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel that is defective in CF, is implicated in multiple cellular functions, including gene regulation. In the present study, using a CFTR-defective pancreatic cancer cell line and its derived subline expressing functional CFTR, we report that MUC4 expression is negatively regulated by CFTR. Short-interfering RNA (siRNA)-mediated silencing of CFTR also leads to an increased expression of MUC4. Additionally, our results suggest that CFTR-mediated regulation of MUC4 is cell densitydependent and is achieved by transcriptional and posttranslational mechanisms. Moreover, in a panel of pancreatic cancer cell lines and normal pancreas, we observed that CFTR was downregulated in pancreatic cancer cells and negatively correlated with MUC4 in most cases. An aberrant expression of MUC4 was also detected in the CF pancreas. Downregulation of CFTR in pancreatic adenocarcinoma and its inverse association with the tumour-linked mucin, MUC4, indicate novel function(s) of CFTR in pancreatic tumour biology and suggest the implication of new signalling pathway(s) in MUC4 regulation.

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Dysregulated expression of MIC-1/PDF in human prostate tumor cells

Cited by 63 publications

References 21 publications

Growth differentiation factor-15 encodes a novel microRNA 3189 that functions as a potent regulator of cell death

Growth differentiation factor-15 encodes a novel microRNA 3189 that functions as a potent regulator of cell death

GDF15 derived from both tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression via Akt and Erk pathways

MUC4 expression is regulated by cystic fibrosis transmembrane conductance regulator in pancreatic adenocarcinoma cells via transcriptional and post-translational mechanisms

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