3479

IGF1

BACKGROUND: Insulin-like growth factor I (IGF-I) can induce epithelial mesenchymal transition (EMT) in many epithelial tumors; however, the molecular mechanism by which this occurs is not clearly understood. Additionally, little is known about the involvement of IGF-I in gastric cancer. METHODS: Two gastric cancer cell lines were treated with IGF-I to induce EMT and levels of transcription factor ZEB2 and microRNA-200c (miR-200c) were measured. Cells were treated with Akt/ERK inhibitors to investigate the role of these pathways in IGF-I-mediated EMT. Transfection of shRNA plasmids was used to silence the ubiquitin ligase Cbl-b to assess its involvement in this process. The relationship between IGF-IR and Cbl-b expression, and the effect of IGF-IR and Cbl-b on metastasis were analyzed in primary gastric adenocarcinoma patients. RESULTS: IGF-I-induced gastric cancer cell EMT was accompanied by ZEB2 up-regulation. Furthermore, both Akt/ERK inhibitors and knockdown of Akt/ERK gene reversed IGF-I-induced ZEB2 up-regulation and EMT through up-regulation of miR-200c, suggesting the involvement of an Akt/ERK-miR-200c-ZEB2 axis in IGF-I-induced EMT. The ubiquitin ligase Cbl-b also ubiquitinated and degraded IGF-IR and inhibited the Akt/ERK-miR-200c-ZEB2 axis, leading to the repression of IGF-I-induced EMT. There was a significant negative correlation between the expression of IGF-IR and Cbl-b in gastric cancer patient tissues (r = -0.265, p < 0.05). More of patients with IGF-IR-positive expression and Cbl-b-negative expression were with lymph node metastasis (p < 0.001). CONCLUSIONS: Together, these findings demonstrate that the ubiquitin ligase Cbl-b represses IGF-I-induced EMT, likely through targeting IGF-IR for degradation and further inhibiting the Akt/ERK-miR-200c-ZEB2 axis in gastric cancer cells.

It has been identified that insulin-like growth factor 1 (IGF-1) activated various pathways of the epithelial-mesenchymal transition (EMT) in a couple of tumors. At the same time, survivin is implicated in EMT of gastric cancer (GC). To date, the impact of survivin on IGF-1-mediated EMT of GC has not been featured. In this work, we used the immunohistochemistry and molecular and cellular experiments to investigate the existence and significance of IGF-1 and survivin. Our findings revealed that survivin protein can be observed in majority of samples in all GC samples. Importantly, survivin expression has an obvious association with GC stage, and metastasis. In vitro, GC cell line BGC823 was treated with different concentrations of IGF-1, resulting in the activation of p-ERK, p-AKT, survivin, and the expression of EMT biomarkers, including N-cadherin, MMP2, and Snail. However, the silencing of survivin eradicated the expression IGF-1-induced EMT biomarkers and affected the migration and invasion of BGC823 cells. In conclusion, IGF-1 signaling activated survivin expression and controlled the expression of EMT biomarkers in the development of GC. This study lays a new stage for the molecular therapy of GC patients in the clinical treatment.

The activation of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) is critical for the induction of epithelial-mesenchymal transition (EMT) by growth factors, including insulin-like growth factor 1 (IGF-1). The activation of intracellular lipogenesis provides proliferative and survival signals for cancer cells. In this study, we investigated the connection between lipogenesis-related EMT processes and IGF-1-mediated PI3K p110 isoform activation in primary (SW480 cells) and metastatic (SW620) colon carcinoma cells. We also examined the underlying signaling pathway that promotes fatty acid synthesis in IGF-1-activated colon cancer cells. IGF-1 stimulation upregulated the expression of lipogenic enzymes as well as the activation of Nardilysin (N-arginine dibasic convertase, NRD1) and its downstream targets, a disintegrin and metalloproteases 10 (ADAM10) and ADAM17. The upregulation of the Lyn/Syk-mediated PI3K p110delta isoform in SW480 cells and the Lyn-dependent PI3K p110alpha isoform in SW620 cells triggered fatty acid production and cell motility in IGF-1-activated colon cancer cells. Pharmacological inhibition with A66 (PI3K p110alpha specific inhibitor) and CAL-101 (PI3K p110delta specific inhibitor) efficiently inhibited EMT in colon cancer cells by blocking the NRD1/ADAM family protein signaling pathway. Gene silencing of NRD1 and ADAM family proteins attenuated the generation of intracellular fatty acid and the migratory activity of colon cancer cells. Our results suggest that the different isoforms of the PI3K p110 subunit could be therapeutic targets for primary and metastatic colon cancer and that regulation of the NRD1/ADAM signaling pathway controls lipogenesis-mediated EMT in IGF-1-stimulated colon cancer cells.

Insulin-like growth factor-1 (IGF-1), a small polypeptide hormone similar to insulin in protein structures, has been identified as an activator of epithelial-mesenchymal transition (EMT) pathways in several types of cancers. As a member of the inhibitor of apoptosis protein (IAP) family, survivin is implicated in the EMT of some cancers. However, the role of survivin on IGF-1-mediated EMT of hepatocellular carcinoma (HCC) has not been clarified. In the present study, we demonstrated that survivin was involved in the EMT process induced by IGF-1 in HCC cell line SMMC7721. With administration of different concentrations of IGF-1, survivin mRNA and protein expression were significantly increased and stimulated EMT in the tested cell line, while the increased invasive and migratory abilities of HCC cells and activation of the EMT process induced by IGF-1 were reversed after silencing of survivin expression by transfecting small interfering RNA. This was further confirmed by the observation of morphological changes, the decrease of invasive and migratory abilities and the downregulation of EMT markers, N-cadherin, vimentin and Snail, and the upregulation of E-cadherin. In conclusion, survivin may play a vital role in the IGF-1 signaling pathway by mediating EMT in HCC through the upregulation of the expression of EMT markers, and the knockdown of survivin expression may suppress the metastasis of HCC, which may provide new insights for the molecular therapy of HCC patients in clinical treatment.

The insulin-like growth factor (IGF) system, which is constituted by the IGF-1 and IGF-2 peptide hormones, their corresponding receptors and several IGF binding proteins, is involved in physiological and pathophysiological processes. The IGF system promotes cancer proliferation/survival and its signaling induces the epithelial-mesenchymal transition (EMT) phenotype, which contributes to the migration, invasiveness, and metastasis of epithelial tumors. These cancers share two major IGF-1R signaling transduction pathways, PI3K/AKT and RAS/MEK/ERK. However, as far as we could review at this time, each type of cancer cell undergoes EMT through tumor-specific routes. Here, we review the tumor-specific molecular signatures of IGF-1-mediated EMT in breast, lung, and gastric cancers.