Growth differentiation factor-15 upregulates interleukin-6 to promote tumorigenesis of prostate carcinoma PC-3 cells

Tsui, Ke‐Hung; Chang, Ying-Ling; Feng, Tsui-Hsia; Chung, Li-Chuan; Lee, Tzu‐Yi; Chang, Phei‐Lang; Juang, Horng‐Heng

doi:10.1530/jme-11-0149

Cited by 42 publications

(33 citation statements)

References 46 publications

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“…GDF15 is an ubiquitous cytokine that belongs to the family of transforming growth factor-beta [65], which modulates cell proliferation, differentiation, apoptosis, invasion and metastasis [66] and is over-expressed in many types of cancer [67–69], especially during the transition from localized to metastatic disease [70–75]. …”

Section: Resultsmentioning

confidence: 99%

Specific gene expression signatures induced by the multiple oncogenic alterations that occur within the PTEN/PI3K/AKT pathway in lung cancer

et al. 2017

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Hyperactivation of the phosphatydil-inositol-3' phosphate kinase (PI3K)/AKT pathway is observed in most NSCLCs, promoting proliferation, migration, invasion and resistance to therapy. AKT can be activated through several mechanisms that include loss of the negative regulator PTEN, activating mutations of the catalytic subunit of PI3K (PIK3CA) and/or mutations of AKT1 itself. However, number and identity of downstream targets of activated PI3K/AKT pathway are poorly defined. To identify the genes that are targets of constitutive PI3K/AKT signalling in lung cancer cells, we performed a comparative transcriptomic analysis of human lung epithelial cells (BEAS-2B) expressing active mutant AKT1 (AKT1-E17K), active mutant PIK3CA (PIK3CA-E545K) or that are silenced for PTEN. We found that, altogether, aberrant PI3K/AKT signalling in lung epithelial cells regulated the expression of 1,960/20,436 genes (9%), though only 30 differentially expressed genes (DEGs) (15 up-regulated, 12 down-regulated and 3 discordant) out of 20,436 that were common among BEAS-AKT1-E17K, BEAS-PIK3CA-E545K and BEAS-shPTEN cells (0.1%). Conversely, DEGs specific for mutant AKT1 were 133 (85 up-regulated; 48 down-regulated), DEGs specific for mutant PIK3CA were 502 (280 up-regulated; 222 down-regulated) and DEGs specific for PTEN loss were 1549 (799 up-regulated, 750 down-regulated). The results obtained from array analysis were confirmed by quantitative RT-PCR on selected up- and down-regulated genes (n = 10). Treatment of BEAS-C cells and the corresponding derivatives with pharmacological inhibitors of AKT (MK2206) or PI3K (LY294002) further validated the significance of our findings. Moreover, mRNA expression of selected DEGs (SGK1, IGFBP3, PEG10, GDF15, PTGES, S100P, respectively) correlated with the activation status of the PI3K/AKT pathway assessed by S473 phosphorylation in NSCLC cell lines (n = 6). Finally, we made use of Ingenuity Pathway Analysis (IPA) to investigate the relevant BioFunctions enriched by the costitutive activation of AKT1-, PI3K- or PTEN-dependent signalling in lung epithelial cells. Expectedly, the analysis of the DEGs common to all three alterations highlighted a group of BioFunctions that included Cell Proliferation of tumor cell lines (14 DEGs), Invasion of cells (10 DEGs) and Migration of tumour cell lines (10 DEGs), with a common core of 5 genes (ATF3, CDKN1A, GDF15, HBEGF and LCN2) that likely represent downstream effectors of the pro-oncogenic activities of PI3K/AKT signalling. Conversely, IPA analysis of exclusive DEGs led to the identification of different downstream effectors that are modulated by mutant AKT1 (TGFBR2, CTSZ, EMP1), mutant PIK3CA (CCND2, CDK2, IGFBP2, TRIB1) and PTEN loss (ASNS, FHL2).These findings not only shed light on the molecular mechanisms that are activated by aberrant signalling through the PI3K/AKT pathway in lung epithelial cells, but also contribute to the identification of previously unrecognised molecules whose regulation takes part in the development of lung cancer.

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Section: Resultsmentioning

confidence: 99%

Specific gene expression signatures induced by the multiple oncogenic alterations that occur within the PTEN/PI3K/AKT pathway in lung cancer

et al. 2017

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“…First, patients with chronic liver diseases had higher GDF-15 concentrations than patients in the control group, and the patients with more severe liver diseases showed proportionally higher GDF-15 values. To date, studies have reported that a high serum GDF-15 value was related to lymph node metastasis and a low survival rate in endometrial cancers5 and increased incidence of oral leukoplakia, squamous cell carcinoma, and prostate cancer 6,7. Additionally, it was reported as the predicting factor of reoccurrence of colorectal cancer8 and the independent predicting factor of the mortality from cardiovascular diseases 9,10.…”

Section: Discussionmentioning

confidence: 99%

Growth Differentiation Factor 15 Predicts Chronic Liver Disease Severity

Lee

Kim

et al. 2017

Gut and Liver

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Background/AimsGrowth differentiation factor 15 (GDF-15) belongs to the transforming growth factor-β superfamily. GDF-15 is emerging as a biomarker for several diseases. The aim of this study was to determine the clinical performances of GDF-15 for the prediction of liver fibrosis and severity in chronic liver disease.MethodsThe serum GDF-15 levels were examined via enzyme immunoassay in 145 patients with chronic liver disease and 101 healthy individuals. The patients with chronic liver disease consisted of 54 patients with chronic hepatitis, 44 patients with compensated liver cirrhosis, and 47 patients with decompensated liver cirrhosis.ResultsOf the patients with chronic liver diseases, the decompensated liver cirrhosis patients had an increased serum GDF-15 (3,483 ng/L) level compared with the patients with compensated liver cirrhosis (1,861 ng/L) and chronic hepatitis (1,232 ng/L). The overall diagnostic accuracies of GDF-15, as determined by the area under the receiver operating characteristic curves, were as follows: chronic hepatitis=0.656 (>574 ng/L, sensitivity, 53.7%; specificity, 79.2%), compensated liver cirrhosis=0.886 (>760 ng/L, sensitivity, 75.6%; specificity, 92.1%), and decompensated liver cirrhosis=0.984 (>869 ng/L, sensitivity, 97.9%; specificity, 94.1%).ConclusionsThis investigation represents the first study to demonstrate the availability of GDF-15 in chronic liver disease. GDF-15 comprised a useful biomarker for the prediction of liver fibrosis and severity in chronic liver disease.

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“…6A and B). GDF-15 is an important growth factor for prostate tumor progression and resistance to cytotoxic agents and radiotherapy in prostate cancer and other cancers (36)(37)(38)(39)(40)(41). Upon GDF-15 silencing (Fig.…”

Section: Identification Of Gdf-15 As a Specific Pace4 Substrate And Pmentioning

confidence: 99%

PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer

et al. 2017

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Inhibition of PACE4, a proprotein convertase that is overexpressed in prostate cancer, has been shown to block cancer progression in an androgen-independent manner. However, the basis for its overexpression and its growth-inhibitory effects are mitigated and uncertain. Here, we report that PACE4 pre-mRNA undergoes DNA methylation-sensitive alternative splicing of its terminal exon 3 0 untranslated region, generating an oncogenic, C-terminally modified isoform (PACE4-altCT). We found this isoform to be strongly expressed in prostate cancer cells, where it displayed an enhanced autoactivating process and a distinct intracellular routing that prevented its extracellular secretion. Together, these events led to a dramatic increase in processing of the progrowth differentiation factor pro-GDF15 as the first PACE4 substrate to be identified in prostate cancer. We detected robust expression of PACE4-altCT in other cancer types, suggesting that an oncogenic switch for this proenzyme may offer a therapeutic target not only in advanced prostate cancer but perhaps also more broadly in human cancer. Cancer Res; 77(24); 6863-79. Ó2017 AACR.

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Growth differentiation factor-15 upregulates interleukin-6 to promote tumorigenesis of prostate carcinoma PC-3 cells

Cited by 42 publications

References 46 publications

Specific gene expression signatures induced by the multiple oncogenic alterations that occur within the PTEN/PI3K/AKT pathway in lung cancer

Specific gene expression signatures induced by the multiple oncogenic alterations that occur within the PTEN/PI3K/AKT pathway in lung cancer

Growth Differentiation Factor 15 Predicts Chronic Liver Disease Severity

PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer

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