IGFBP-2/PTEN: A critical interaction for tumours and for general physiology?

Zeng, Li; Perks, Claire M; Holly, Jeffrey M P

doi:10.1016/j.ghir.2015.01.003

Cited by 17 publications

(20 citation statements)

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“…Of particular interest is the interaction of IGFBP-2 with phosphatase and tensin 263 homolog (PTEN), a tumour suppressor that inhibits PI3 kinase/Akt signalling. PTEN down-264 regulated IGFBP-2 expression in cancer cells, and high IGFBP-2 levels were associated with low 265 PTEN levels in aggressive cancers (Zeng, et al 2015). In turn, IGFBP-2 suppressed PTEN activity 266 via an integrin-mediated mechanism in normal and cancer cells, and interaction of IGFBP-2 with 267 RPTP β on the cell surface also contributed to this inhibition.…”

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confidence: 99%

40 YEARS OF IGF1: IGF-binding proteins

Bach

2018

Journal of Molecular Endocrinology

192

111

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Insulin-like growth factor binding proteins (IGFBPs) 1-6 bind IGFs but not insulin with high affinity. They were initially identified as serum carriers and passive inhibitors of IGF actions.However, subsequent studies showed that, although IGFBPs inhibit IGF actions in many circumstances, they may also potentiate these actions. IGFBPs are widely expressed in most tissues, and they are flexible endocrine and autocrine/paracrine regulators of IGF activity, which is essential for this important physiological system. More recently, individual IGFBPs have been shown to have IGF-independent actions. Mechanisms underlying these actions include (i) interaction with non-IGF proteins in compartments including the extracellular space and matrix, the cell surface and intracellularly; (ii) interaction with and modulation of other growth factor pathways including EGF, TGF-β and VEGF; and (iii) direct or indirect transcriptional effects following nuclear entry of IGFBPs. Through these IGF-dependent and IGF-independent actions, IGFBPs modulate essential cellular processes including proliferation, survival, migration, senescence, autophagy and angiogenesis. They have been implicated in a range of disorders including malignant, metabolic, neurological and immune diseases. A more complete understanding of their cellular roles may lead to the development of novel IGFBP-based therapeutic opportunities.Page 2 of 51 3The somatomedin hypothesis, which postulated that growth hormone activity was mediated by a 1 serum factor, was published in 1957 (Salmon and Daughaday 1957). In the 1960s, several 2 circulating somatomedin activities were identified and attributed to peptides sized 5~8 kDa that had 3 both growth promoting and insulin-like metabolic effects. A paradox of these early observations 4 was that normoglycaemia was maintained in vivo despite the circulating concentrations of 5 somatomedins being sufficient to cause profound hypoglycaemia. Following the purification of 6 these small somatomedin peptides, it was observed that almost all of the circulating somatomedin 7 activity was found in a number of chromatographic peaks with apparent molecular weights greater 8 than 30~40 kDa and further studies indicated that this was due to binding by plasma binding 9proteins (Hintz and Liu 1977;Megyesi, et al. 1975;Zapf, et al. 1975). The apparent hypoglycaemia 10 paradox could then be resolved if somatomedin activity was inhibited by association with these 11 binding proteins. Of note, these early studies already demonstrated that insulin did not bind to these 12 proteins. 13 14In the following years, the somatomedin activities were identified as IGF-I and IGF-II, and they 15 were sequenced and cloned. IGF binding proteins (IGFBPs) 1-3 were the first to be identified and 16 purified, with IGFBPs 4-6 being subsequently described (Rajaram, et al. 1997;Rechler 1993). By 17 the early 1990s, all six members of this high affinity IGFBP family had been cloned and a number 18 of key structural and sequence similarities identified. Addition...

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confidence: 99%

40 YEARS OF IGF1: IGF-binding proteins

Bach

2018

Journal of Molecular Endocrinology

192

111

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“…Because of the potential for DNA methylation alterations to modify gene expression, we next assessed the methylation status of CpGs located in genes associated with signaling pathways and biological mediators implicated in obesity-associated cancers [17, 32, 33] in the esophageal tissues from the subjects with low vs. high BMI. With regard to the insulin and insulin growth factor 1 (IGF-1) related pathways, we observed increased methylation of IGFBP1 (average beta = 0.11 in low BMI cases and 0.27 in high BMI cases) and IRS2 (average beta = 0.11 in low BMI cases and 0.36 in high BMI cases) in the high BMI compared to low BMI BE cases.…”

Section: Resultsmentioning

confidence: 99%

Global DNA methylation patterns in Barrett’s esophagus, dysplastic Barrett’s, and esophageal adenocarcinoma are associated with BMI, gender, and tobacco use

et al. 2016

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BackgroundThe risk of developing Barrett’s esophagus (BE) and/or esophageal adenocarcinoma (EAC) is associated with specific demographic and behavioral factors, including gender, obesity/elevated body mass index (BMI), and tobacco use. Alterations in DNA methylation, an epigenetic modification that can affect gene expression and that can be influenced by environmental factors, is frequently present in both BE and EAC and is believed to play a role in the formation of BE and its progression to EAC. It is currently unknown whether obesity or tobacco smoking influences the risk of developing BE/EAC via the induction of alterations in DNA methylation. To investigate this possibility, we assessed the genome-wide methylation status of 81 esophageal tissues, including BE, dysplastic BE, and EAC epithelia using HumanMethylation450 BeadChips (Illumina).ResultsWe found numerous differentially methylated loci in the esophagus tissues when comparing males to females, obese to lean individuals, and smokers to nonsmokers. Differences in DNA methylation between these groups were seen in a variety of functional genomic regions and both within and outside of CpG islands. Several cancer-related pathways were found to have differentially methylated genes between these comparison groups.ConclusionsOur findings suggest obesity and tobacco smoking may influence DNA methylation in the esophagus and raise the possibility that these risk factors affect the development of BE, dysplastic BE, and EAC through influencing the epigenetic status of specific loci that have a biologically plausible role in cancer formation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0273-7) contains supplementary material, which is available to authorized users.

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“…In pleural effusions, where PAPP‐A is close to 50‐fold elevated as compared to serum, the degradation of IGFBP‐2 remains similar to that in serum and in serum from lung cancer patients the major part of IGFBP‐2 circulates in its free form (data in preparation). On the basis of our recent and present data, we speculate that in vivo, IGFBP‐2 is primarily unoccupied and hence not only protected against PAPP‐A degradation but also able to suppress PTEN . Another issue that remains to be investigated is whether the relationship between PAPP‐A and IGFBP‐2 serum concentrations is causal.…”

Section: Discussionmentioning

confidence: 68%

Prognostic relevance and performance characteristics of serum IGFBP‐2 and PAPP‐A in women with breast cancer: a long‐term Danish cohort study

et al. 2018

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Measurement of circulating insulin‐like growth factors (IGFs), in particular IGF‐binding protein (IGFBP)‐2, at the time of diagnosis, is independently prognostic in many cancers, but its clinical performance against other routinely determined prognosticators has not been examined. We measured IGF‐I, IGF‐II, pro‐IGF‐II, IGF bioactivity, IGFBP‐2, ‐3, and pregnancy‐associated plasma protein A (PAPP‐A), an IGFBP regulator, in baseline samples of 301 women with breast cancer treated on four protocols (Odense, Denmark: 1993–1998). We evaluated performance characteristics (expressed as area under the curve, AUC) using Cox regression models to derive hazard ratios (HR) with 95% confidence intervals (CIs) for 10‐year recurrence‐free survival (RFS) and overall survival (OS), and compared those against the clinically used Nottingham Prognostic Index (NPI). We measured the same biomarkers in 531 noncancer individuals to assess multidimensional relationships (MDR), and evaluated additional prognostic models using survival artificial neural network (SANN) and survival support vector machines (SSVM), as these enhance capture of MDRs. For RFS, increasing concentrations of circulating IGFBP‐2 and PAPP‐A were independently prognostic [HR biomarker doubling: 1.474 (95% CIs: 1.160, 1.875, P = 0.002) and 1.952 (95% CIs: 1.364, 2.792, P < 0.001), respectively]. The AUCRFS for NPI was 0.626 (Cox model), improving to 0.694 (P = 0.012) with the addition of IGFBP‐2 plus PAPP‐A. Derived AUCRFS using SANN and SSVM did not perform superiorly. Similar patterns were observed for OS. These findings illustrate an important principle in biomarker qualification—measured circulating biomarkers may demonstrate independent prognostication, but this does not necessarily translate into substantial improvement in clinical performance.

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IGFBP-2/PTEN: A critical interaction for tumours and for general physiology?

Cited by 17 publications

References 61 publications

40 YEARS OF IGF1: IGF-binding proteins

40 YEARS OF IGF1: IGF-binding proteins

Global DNA methylation patterns in Barrett’s esophagus, dysplastic Barrett’s, and esophageal adenocarcinoma are associated with BMI, gender, and tobacco use

Prognostic relevance and performance characteristics of serum IGFBP‐2 and PAPP‐A in women with breast cancer: a long‐term Danish cohort study

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