MicroRNA-214 Reduces Insulin-like Growth Factor-1 (IGF-1) Receptor Expression and Downstream mTORC1 Signaling in Renal Carcinoma Cells

Abstract

Renal cell carcinoma (RCC)5 accounts for nearly 3% of all malignancies. Among the five histologic subtypes, clear cell renal carcinoma accounts for about 85% of all RCCs (1, 2). About 30% of patients show renal cancer metastasis to lung, liver, bone, and brain at the time of diagnosis, and half of the remaining patients eventually develop metastasis (3-5). Individuals bearing germ line mutation in the von Hippel-Lindau (VHL) tumor suppressor gene located on chromosome 3p have increased risk for clear cell RCC. Inherited forms of RCC occur when the remaining wild type VHL allele is lost.Apart from inactivated VHL-driven tumorigenesis, IGF-1 signal transduction significantly contributes to the growth of RCC cells in vitro and in vivo in animal models (6, 7). In fact, increased IGF-1 mRNA and protein levels in the kidney are significantly higher in RCC in humans (8, 9). Similarly, IGF-1 receptor (IGF-1R) expression has also been shown to be significantly associated with increased risk of RCC (10, 11). Also, patients with IGF-1R-positive RCC showed significantly reduced survival rates (12, 13). The dimeric IGF-1R shares significantly high homology with insulin receptor. IGF-1R is produced as a single polypeptide, which is cleaved to form the mature ␣-and ␤-subunits. The ␣-protein represents the transmembrane protein with extracellular domain, whereas the ␤-subunit is exclusively intracellular. The IGF-1 binds to the extracellular domain of ␣-subunit, resulting in heterotetramerization. Upon ligand binding, conformational change in the juxtamembrane domain induces an increase in tyrosine kinase activity of the ␤-subunit, which autophosphorylates specific tyrosine residues in the ␤-subunit. Tyrosine-phosphorylated ␤-subunit recruits the IRS protein through binding to its N-terminal PTB domain. Receptor-bound IRS protein serves as docking sites for the Src homology 2 domain-containing proteins, which trigger signal transduction to induce tumor growth of RCC mainly by two arms, the Ras/MAPK and phosphatidylinositol 3-kinase/Akt pathways (14, 15). Because of significant homology between IGF-1R and insulin receptor, they can form a hybrid receptor, which binds IGF-1 with an affinity similar to that with IGF-1R heterotetramer alone, and can elicit mitogenic signal transduction in tumor cells (14,15). Therefore, * This work was supported in part by the Veterans Affairs Research Service Merit Review Grant 2 I01 BX000926 and National Institutes of Health Grant RO1 DK50190 (to G. G. C.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We dedicate this paper to Dr. Hanna E. Abboud, who unexpectedly left us on January 7, 2015. His continued encouragement and support were vital for the completion of this work. 1 Both authors contributed equally to this work. 2 Supported by Veterans Affairs Merit Review Grant 5I01BX001340. 3 Supported by V...

The E3 ubiquitin ligase Cbl-b inhibits tumor growth in multidrug-resistant gastric and breast cancer cells

“…Emerging evidence suggests that IGF-1R could drive renal cancer cell proliferation [25]. Furthermore, miR-133a has been shown to prevent cell proliferation in human osteosarcoma cells by inhibiting IGF-1R expression and Akt/ERK signaling activation [26].…”

Emerging Role of MicroRNAs in mTOR Signaling

“…Increased IGF-1/IGF-1R level in turn results in phosphorylation and inactivation of PRAS40 in an AKT-dependent manner, leading to activation of mTORC1 signal transduction to increase phosphorylation of S6 kinase and 4E-BP1. Reintroduction of miR-214 significantly inhibits the AKT/PRAS40/mTORC1 axis in the IGF-1R signaling cascade, which dampens renal cancer cell proliferation [73] .…”

Insulin Resistance in Kidney Disease: Is There a Distinct Role Separate from That of Diabetes or Obesity

“…In this context, the routine metabolic signaling that regulates insulin-dependent glucose transport/utilization can occur in opposition to growth signaling pathways that are also dependent on insulin. These pathways include serine kinases that are redox-sensitive, including extracellular receptor kinase, Rho kinase, JUN NH 2 -terminal kinase, and the mammalian target of rapamycin/serine kinase 1 signaling pathways [11,12,13,14,15,16,17] that regulate growth, hypertrophy, and fibrotic pathways. These pathways are also under the control of other neurohumoral pathways in insulin-resistant states, i.e., the sympathetic nervous system and the renin-angiotensin-aldosterone system [10,18,19].…”