IGFBP-rP1 induces p21 expression through a p53-independent pathway, leading to cellular senescence of MCF-7 breast cancer cells

Zuo, Shuguang; Liu, Chang; Wang, Jianguo; Wang, Fuqing; Xu, Weixin; Cui, Shao; Liu, Yuan; Chen, Xudong; Fan, Wei; Cui, Ming-chen; Song, Guohua

doi:10.1007/s00432-012-1153-y

Cited by 52 publications

(38 citation statements)

References 36 publications

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“…Importantly, both TIMP-2 and IGFBP7 appear to be able to signal in autocrine and paracrine fashions [24,27-30] thus spreading the 'alarm' from the site of injury. In terms of timing, this signal could be ideal as it may be early enough that treatment can still alter the outcome - further study will be required to test this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

et al. 2013

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IntroductionAcute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI.MethodsWe performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection.ResultsModerate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P <0.002), none of which achieved an AUC >0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method.ConclusionsTwo novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI.Trial registrationClinicalTrials.gov number NCT01209169.

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Section: Discussionmentioning

confidence: 99%

Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

et al. 2013

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“…This hypothesis is grounded in data from in vitro studies of colon and breast cancer cell lines, which have shown the capacity of IGFBP7 to induce G 1 cell cycle arrest and senescence, as well as a study of melanocyte and melanoma cell lines, which has shown that IGFBP7 regulates proliferation and senescence (80,81). These studies have reported that the effects of IGFBP7 are mediated by increased expression of p21 and p53 as well as inhibition of mitogen-activated protein kinase signaling (80)(81)(82). However, it is also plausible that elevated IGFBP7 could have a deleterious effect on the injured kidney, because IGFBP7 is an IGF-1 receptor antagonist (83).…”

Section: Igfbp7mentioning

confidence: 99%

Biomarkers of AKI

Alge

Arthur

2015

Clinical Journal of the American Society of Nephrology

271

188

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AKI is a common clinical condition associated with a number of adverse outcomes. More timely diagnosis would allow for earlier intervention and could improve patient outcomes. The goal of early identification of AKI has been the primary impetus for AKI biomarker research, and has led to the discovery of numerous novel biomarkers. However, in addition to facilitating more timely intervention, AKI biomarkers can provide valuable insight into the molecular mechanisms of this complex and heterogeneous disease. Furthermore, AKI biomarkers could also function as molecular phenotyping tools that could be used to direct clinical intervention. This review highlights the major studies that have characterized the diagnostic and prognostic predictive power of these biomarkers. The mechanistic relevance of neutrophil gelatinase-associated lipocalin, kidney injury molecule 1, IL-18, livertype fatty acid-binding protein, angiotensinogen, tissue inhibitor of metalloproteinase-2, and IGF-binding protein 7 to the pathogenesis and pathobiology of AKI is discussed, putting these biomarkers in the context of the progressive phases of AKI. A biomarker-integrated model of AKI is proposed, which summarizes the current state of knowledge regarding the roles of these biomarkers and the molecular and cellular biology of AKI.

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“…19 Several IGF-independent effects, such as tumor suppression in melanoma and colon cancer, and induction of cell senescence in breast cancer lines, are also ascribed to IGFBP7. 2021 …”

Section: Biological Functions Of Timp-2 and Igfbp7mentioning

confidence: 99%

Clinical Use of the Urine Biomarker [TIMP-2] × [IGFBP7] for Acute Kidney Injury Risk Assessment

Nolin

Faubel

Askenazi

et al. 2016

American Journal of Kidney Diseases

189

147

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Acute kidney injury (AKI) is a devastating complication commonly occurring in the critically ill population with devastating short- and long-term consequences. Despite standardization of the definition and staging of AKI, early recognition remains challenging given that serum creatinine (Scr) is a marker—albeit imperfect—of kidney function and not kidney injury. Furthermore, the delay in rise of Scr after loss of glomerular filtration also prevents timely detection of decreased kidney function in patients with AKI. Over the past decade, numerous clinical investigations have evaluated the utility of several biomarkers in the early diagnosis and risk stratification of AKI. In 2014, the US Food and Drug Administration (FDA) approved the marketing of a test based on the combination of the urine concentrations of tissue inhibitor of metalloproteinase 2 and insulin-like growth factor binding protein 7 ([TIMP-2]x[IGFBP7]) to determine if certain critically ill patients are at risk of developing moderate to severe AKI. The optimal role of this biomarker in diagnosis, management, and prognosis of AKI in different clinical settings requires further clarification. In this perspective, we summarize the biological actions of these two cell-cycle arrest biomarkers, and present important considerations regarding the clinical application, interpretation, and limitations of this novel test for the early detection AKI.

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IGFBP-rP1 induces p21 expression through a p53-independent pathway, leading to cellular senescence of MCF-7 breast cancer cells

Cited by 52 publications

References 36 publications

Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

Biomarkers of AKI

Clinical Use of the Urine Biomarker [TIMP-2] × [IGFBP7] for Acute Kidney Injury Risk Assessment

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