Regulation of protumorigenic pathways by Insulin like growth factor binding protein2 and its association along with β-catenin in breast cancer lymph node metastasis

Sehgal, Priyanka; Kumar, Neeraj; Kumar, V. R. Praveen; Patil, Shilpa; Bhattacharya, Animesh; Kumar, Manavalan Vijaya; Mukherjee, Geetashree; Kondaiah, Paturu

doi:10.1186/1476-4598-12-63

Cited by 28 publications

(18 citation statements)

References 48 publications

(54 reference statements)

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“…IGFBP2 is highly up regulated in GBM and its expression has been shown to be associated with increased cellular migration and invasion of several cancers [3][4][5][6][7][8][9]. Increased levels of IGFBP2 in GBM tissue and patient serum are potential diagnostic and prognostic markers [10,11].…”

Section: Introductionmentioning

confidence: 99%

Novel anti IGFBP2 single chain variable fragment inhibits glioma cell migration and invasion

et al. 2015

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Insulin like growth factor binding protein 2 (IGFBP2) is highly up regulated in glioblastoma (GBM) tissues and has been one of the prognostic indicators. There are compelling evidences suggesting important roles for IGFBP2 in glioma cell proliferation, migration and invasion. Extracellular IGFBP2 through its carboxy terminal arginine glycine aspartate (RGD) motif can bind to cell surface α5β1 integrins and activate pathways downstream to integrin signaling. This IGFBP2 activated integrin signaling is known to play a crucial role in IGFBP2 mediated invasion of glioma cells. Hence a molecular inhibitor of carboxy terminal domain of IGFBP2 which can inhibit IGFBP2-cell surface interaction is of great therapeutic importance. In an attempt to develop molecular inhibitors of IGFBP2, we screened single chain variable fragment (scFv) phage display libraries, Tomlinson I (Library size 1.47 × 10(8)) and Tomlinson J (Library size 1.37 × 10(8)) using human recombinant IGFBP2. After screening we obtained three IGFBP2 specific binders out of which one scFv B7J showed better binding to IGFBP2 at its carboxy terminal domain, blocked IGFBP2-cell surface association, reduced activity of matrix metalloprotease 2 in the conditioned medium of glioma cells and inhibited IGFBP2 induced migration and invasion of glioma cells. We demonstrate for the first time that in vitro inhibition of extracellular IGFBP2 activity by using human scFv results in significant reduction of glioma cell migration and invasion. Therefore, the inhibition of IGFBP2 can serve as a potential therapeutic strategy in the management of GBM.

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Section: Introductionmentioning

confidence: 99%

Novel anti IGFBP2 single chain variable fragment inhibits glioma cell migration and invasion

et al. 2015

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“…An IHC study on resected BC tissues showed a gradual elevation in IGFBP-2 expression from atypical hyperplasia through to carcinoma in situ and invasive carcinoma [35] and a TMA analysis of more than 4,000 primary invasive breast tumours indicated that an adverse survival outcome is correlated with IGFBP-2 expression in ERα negative tumours [41]. IGFBP-2 expression combined with cell adhesion protein, β-catenin, is linked with lymph node metastasis in BCs [42] and high levels of IGFBP-2 expression together with loss of PTEN expression are also associated with triple negative (TN) BC and poor survival rates [43]. IGFBP-2 is up-regulated in an in vitro model of Her-2+ BC [44] and recently multiple antigenic peptides (MAPs) comprising IGFBP-2 epitopes have been used to block tumour progression in a transgenic mouse model [37, 45].…”

Section: Discussionmentioning

confidence: 99%

Deregulation of IGF-binding proteins -2 and -5 contributes to the development of endocrine resistant breast cancerin vitro

et al. 2016

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Tamoxifen (TAM) remains the adjuvant therapy of choice for pre-menopausal women with ERα-positive breast cancer. Resistance and recurrence remain, however, a major challenge with many women relapsing and subsequently dying. The insulin-like growth factor (IGF) axis is involved in breast cancer pathogenesis and progression to endocrine resistant disease, but there is very little data on the expression and potential role of IGF-binding proteins (IGFBP) during acquisition of the resistant phenotype. The aim of this study was to determine the expression and functional role of IGFBP-2 and -5 in the development of TAM resistance (TamR) in vitro and to test retrospectively whether they were predictive of resistance in a tissue microarray of 77 women with primary breast cancers who relapsed on/after endocrine therapy and 193 who did not with long term follow up. Reciprocal expression of IGFBP-2 and IGFBP-5 was observed at both mRNA and protein level in TamR cells. IGFBP-2 expression was increased by 10-fold while IGFBP-5 was decreased by 100-fold, compared to TAM-sensitive control cells. shRNA-mediated silencing of IGFBP-2 in TamR cells restored TAM sensitivity suggesting a causal role for this gene in TamR. While silencing of IGFBP-5 in control cells had no effect on TAM sensitivity, it significantly increased the migratory capacity of these cells. Quantitative image analysis of immunohistochemical data failed, however, to demonstrate an effect of IGFBP2 expression in endocrine-relapsed patients. Likewise, IGFBP-2 and IGFBP-5 expression failed to show any significant associations with survival either in patients relapsing or those not relapsing on/after endocrine therapy. By contrast, in silico mining of a separate published dataset showed that in patients who received endocrine treatment, loss of expression of IGBP-5 was significantly associated with worse survival. Overall these data suggest that co-ordinated and reciprocal alteration in IGFBP-2 and −5 expression may play a role in the acquisition of endocrine resistance.

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“…The Wnt signaling pathway is activated when the above homeostasis was broken resulting in an excess of β-catenin in hepatocytes. β-catenin also binds to transcription factors such as TCf/LEf to form a heterodimer and this regulates related target genes such as MMP-9, cyclin D1, c-myc and COX-2 (36)(37)(38). Thus, β-catenin regulates hepatocyte proliferation through the above process.…”

Section: Mirna Microarray Gene Microarray ---------------------------mentioning

confidence: 99%

Integrated analysis of differentially expressed mRNAs and miRNAs between hepatocellular carcinoma and their matched adjacent normal liver tissues

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et al. 2015

Oncology Reports

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Hepatocellular carcinoma has a high mortality rate, thus, there is a need for improvement of prognosis of such patients. The aim of the present study was to identify differentially expressed mRNAs and miRNAs between hepatocellular carcinoma tissues and their matched adjacent normal liver tissues, and to carry out a bioinformatics analysis. Agilent 8x60K microarray technology was used to detect the changes of mRNA and miRNA expression between hepatocellular carcinoma tissues and their matched adjacent normal liver tissues. To select differentially expressed mRNAs and miRNAs, gene ontology (GO) and pathway analysis were performed using bioinformatics methods. qPCR was used to verify the microarray data. As a result, 924 mRNAs and 21 miRNAs exhibited a higher expression in the hepatocellular carcinoma tissue than their matched adjacent normal liver tissue. In comparison with the adjacent normal tissue, the carcinoma tissue showed a downregulated expression of 1,770 mRNAs and 12 miRNAs. The GO and pathway analysis showed that these RNAs were involved in the transcription process, REDOX, signal transduction, ion transport, immune response, cell adhesion and binding functions. A total of 572 target genes of 14 miRNAs were identified, most of which were involved in tumors. The results of qPCR were in concordance with the microarray results. In summary, the differentially expressed mRNAs and miRNAs that include signal transduction, immune response and many other key links may provide novel targets for early diagnosis and therapy of hepatocellular carcinoma.

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Regulation of protumorigenic pathways by Insulin like growth factor binding protein2 and its association along with β-catenin in breast cancer lymph node metastasis

Cited by 28 publications

References 48 publications

Novel anti IGFBP2 single chain variable fragment inhibits glioma cell migration and invasion

Novel anti IGFBP2 single chain variable fragment inhibits glioma cell migration and invasion

Deregulation of IGF-binding proteins -2 and -5 contributes to the development of endocrine resistant breast cancerin vitro

Integrated analysis of differentially expressed mRNAs and miRNAs between hepatocellular carcinoma and their matched adjacent normal liver tissues

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