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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Biol+Chem
2016 ; 291
(28
): 14662-76
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MicroRNA-214 Reduces Insulin-like Growth Factor-1 (IGF-1) Receptor Expression and
Downstream mTORC1 Signaling in Renal Carcinoma Cells
#MMPMID27226530
Das F
; Dey N
; Bera A
; Kasinath BS
; Ghosh-Choudhury N
; Choudhury GG
J Biol Chem
2016[Jul]; 291
(28
): 14662-76
PMID27226530
show ga
Elevated IGF-1/insulin-like growth factor-1 receptor (IGF-1R) autocrine/paracrine
signaling in patients with renal cell carcinoma is associated with poor prognosis
of the disease independent of their von Hippel-Lindau (VHL) status. Increased
expression of IGF-1R in renal cancer cells correlates with their potency of tumor
development and progression. The mechanism by which expression of IGF-1R is
increased in renal carcinoma is not known. We report that VHL-deficient and
VHL-positive renal cancer cells possess significantly decreased levels of mature,
pre-, and pri-miR-214 than normal proximal tubular epithelial cells. We
identified an miR-214 recognition element in the 3'UTR of IGF-1R mRNA and
confirmed its responsiveness to miR-214. Overexpression of miR-214 decreased the
IGF-1R protein levels, resulting in the inhibition of Akt kinase activity in both
types of renal cancer cells. IGF-1 provoked phosphorylation and inactivation of
PRAS40 in an Akt-dependent manner, leading to the activation of mTORC1 signal
transduction to increase phosphorylation of S6 kinase and 4EBP-1.
Phosphorylation-deficient mutants of PRAS40 and 4EBP-1 significantly inhibited
IGF-1R-driven proliferation of renal cancer cells. Expression of miR-214
suppressed IGF-1R-induced phosphorylation of PRAS40, S6 kinase, and 4EBP-1,
indicating inhibition of mTORC1 activity. Finally, miR-214 significantly blocked
IGF-1R-forced renal cancer cell proliferation, which was reversed by expression
of 3'UTR-less IGF-1R and constitutively active mTORC1. Together, our results
identify a reciprocal regulation of IGF-1R levels and miR-214 expression in renal
cancer cells independent of VHL status. Our data provide evidence for a novel
mechanism for IGF-1R-driven renal cancer cell proliferation involving miR-214 and
mTORC1.