Differential expression of IGF-1 mRNA isoforms in colorectal carcinoma and normal colon tissue

Kasprzak, Aldona; Szaflarski, Witold; Szmeja, Jacek; Andrzejewska, Małgorzata; Przybyszewska, Wiesława; Kaczmarek, Elżbieta; Koczorowska, Maria Magdalena; Kościński, Tomasz; Zabel, Maciej; Drews, Michał

doi:10.3892/ijo.2012.1706

Cited by 22 publications

(40 citation statements)

References 46 publications

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“…Whereas in colorectal carcinoma, the local expression levels of total IGF-1 mRNA and all splicing isoforms of IGF-1 mRNA were decreased as compared to normal colon tissues. The results of this study suggest an increased regenerative potential in normal colon tissues which, at least partially, is linked to an elevated expression of total IGF-1 mRNA and its isoform A (8). An important clue to the essential role of the IGF-1R in cellular function was uncovered by Sell and co-workers who reported that IGF-1 signaling is an absolute requirement for viral transformation of cells (13).…”

Section: Igf Axis and Cancermentioning

confidence: 73%

“…Furthermore, it has been shown in two independent studies that human Eb-peptide cleaved form human pre-pro-IGF1b, which is 77 amino acids long, localized to the nuclei of transfected cells and may have IGF-1 independent mitogenic and bioactive properties (4–6). Notably, a 10-fold decrease in the IGF-1B transcript level was observed (7), and a downshift of the IGF-1B content in favor of the IGF-1A isoform was reported when non-tumor tissue and colorectal cancer cells were analyzed (8). On the other hand, an increase in IGF-1B and decrease in IGF-1A expression were found in cervical cancer and control cells, respectively (9).…”

Section: Introductionmentioning

confidence: 99%

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IGF axis and other factors in HPV-related and HPV-unrelated carcinogenesis (Review)

Durzyńska

2014

Oncology Reports

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The insulin-like growth factor (IGF) axis promotes the growth of cells, tissues and organs. IGF-1 is mainly produced in the liver but is also secreted from local tissues. In the circulation, IGF-1 is bound to insulin-like binding proteins (IGFBPs), and when released it activates the insulin-like growth factor receptor (IGF-1R). The signal is further transmitted by intracellular signaling pathways leading to gene expression that regulates, among others, cell proliferation and survival. This review presents the IGF axis in the context of cell transformation and cancer development. Aspects involving IGF-1 deficiency and protection from cancer are also briefly described. Furthermore, human papillomaviruses (HPVs) interplaying with IGF axis components in cervical cancer development are described. These small dsDNA viruses are divided into low-risk and high-risk HPVs with regard to the potency of their oncogenic actions; they mainly infect epithelial or mucosal cells. Special attention is drawn to expression of two major HPV oncogenes (E6 and E7) initiating and maintaining cervical carcinogenesis, which is a multistep and multifactorial process; therefore, involvement of additional factors such as mitochondrial DNA changes, sex hormones, retinoic and folic acids are also discussed. Finally, IGF axis components and HPV oncogenes as targets in anticancer treatment are presented which include IGF-1R downregulation, RNA interference and anti-HPV therapeutic vaccines. The review concludes that despite an enormous advancement in research on IGF and HPV-related cancers, more molecular studies and clinical trials are needed before commercialized therapies are widely available for oncology patients.

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Section: Igf Axis and Cancermentioning

confidence: 73%

Section: Introductionmentioning

confidence: 99%

IGF axis and other factors in HPV-related and HPV-unrelated carcinogenesis (Review)

Durzyńska

2014

Oncology Reports

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“…Several target proteins were chosen as selectivity counter-screens, including TNF-alpha, FGF-2, G-CSF, IGF-1, and EPO. Similar to that of VEGF, the expression levels of these proteins are post-transcriptionally regulated, either through a 5’-UTR IRES, 3’-UTR AU-rich elements (AREs), or both [31–39]. …”

Section: Resultsmentioning

confidence: 99%

Discovery of Novel Small Molecule Inhibitors of VEGF Expression in Tumor Cells Using a Cell-Based High Throughput Screening Platform

et al. 2016

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Current anti-VEGF (Vascular Endothelial Growth Factor A) therapies to treat various cancers indiscriminately block VEGF function in the patient resulting in the global loss of VEGF signaling which has been linked to dose-limiting toxicities as well as treatment failures due to acquired resistance. Accumulating evidence suggests that this resistance is at least partially due to increased production of compensatory tumor angiogenic factors/cytokines. VEGF protein production is differentially controlled depending on whether cells are in the normal “homeostatic” state or in a stressed state, such as hypoxia, by post-transcriptional regulation imparted by elements in the 5’ and 3’ untranslated regions (UTR) of the VEGF mRNA. Using the Gene Expression Modulation by Small molecules (GEMS™) phenotypic assay system, we performed a high throughput screen to identify low molecular weight compounds that target the VEGF mRNA UTR-mediated regulation of stress-induced VEGF production in tumor cells. We identified a number of compounds that potently and selectively reduce endogenous VEGF production under hypoxia in HeLa cells. Medicinal chemistry efforts improved the potency and pharmaceutical properties of one series of compounds resulting in the discovery of PTC-510 which inhibits hypoxia-induced VEGF expression in HeLa cells at low nanomolar concentration. In mouse xenograft studies, oral administration of PTC-510 results in marked reduction of intratumor VEGF production and single agent control of tumor growth without any evident toxicity. Here, we show that selective suppression of stress-induced VEGF production within tumor cells effectively controls tumor growth. Therefore, this approach may minimize the liabilities of current global anti-VEGF therapies.

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“…A differential expression profile of the IGF-I isoforms have been shown in various conditions or pathologies in humans, such as skeletal muscle damage (31,68), endometriosis (35) or prostate (34), cervical (69) and colorectal cancer (137). The diversity and the patterns of differential expression have been proposed to reflect potential biological activities associated with the E domain peptides (27,52).…”

Section: Igf-i Peptides Actions and Signalingmentioning

confidence: 99%

The Complexity of the IGF1 Gene Splicing, Posttranslational Modification and Bioactivity

Philippou

Maridaki

Pneumaticos

et al. 2014

Mol Med

100

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The insulinlike growth factor-I (IGF-I) is an important factor which regulates a variety of cellular responses in multiple biological systems. The IGF1 gene comprises a highly conserved sequence and contains six exons, which give rise to heterogeneous mRNA transcripts by a combination of multiple transcription initiation sites and alternative splicing. These multiple transcripts code for different precursor IGF-I polypeptides, namely the IGF-IEa, IGF-IEb and IGF-IEc isoforms in humans, which also undergo posttranslational modifications, such as proteolytic processing and glycosylation. IGF-I actions are mediated through its binding to several cell-membrane receptors and the IGF-I domain responsible for the receptor binding is the bioactive mature IGF-I peptide, which is derived after the posttranslational cleavage of the pro-IGF-I isoforms and the removal of their carboxy-terminal E-peptides (that is, the Ea, Eb and Ec). Interestingly, differential biological activities have been reported for the different IGF-I isoforms, or for their E-peptides, implying that IGF-I peptides other than the IGF-I ligand also possess bioactivity and, thus, both common and unique or complementary pathways exist for the IGF-I isoforms to promote biological effects. The multiple peptides derived from IGF-I and the differential expression of its various transcripts in different conditions and pathologies appear to be compatible with the distinct cellular responses observed to the different IGF-I peptides and with the concept of a complex and possibly isoform-specific IGF-I bioactivity. This concept is discussed in the present review, in the context of the broad range of modifications that this growth factor undergoes which might regulate its mechanism(s) of action.

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Differential expression of IGF-1 mRNA isoforms in colorectal carcinoma and normal colon tissue

Cited by 22 publications

References 46 publications

IGF axis and other factors in HPV-related and HPV-unrelated carcinogenesis (Review)

IGF axis and other factors in HPV-related and HPV-unrelated carcinogenesis (Review)

Discovery of Novel Small Molecule Inhibitors of VEGF Expression in Tumor Cells Using a Cell-Based High Throughput Screening Platform

The Complexity of the IGF1 Gene Splicing, Posttranslational Modification and Bioactivity

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