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2015 ; 34
(11
): 1463-74
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LNK (SH2B3): paradoxical effects in ovarian cancer
#MMPMID24704825
Ding LW
; Sun QY
; Lin DC
; Chien W
; Hattori N
; Dong XM
; Gery S
; Garg M
; Doan NB
; Said JW
; Xiao JF
; Yang H
; Liu LZ
; Meng X
; Huang RY
; Tang K
; Koeffler HP
Oncogene
2015[Mar]; 34
(11
): 1463-74
PMID24704825
show ga
LNK (SH2B3) is an adaptor protein studied extensively in normal and malignant
hematopoietic cells. In these cells, it downregulates activated tyrosine kinases
at the cell surface resulting in an antiproliferative effect. To date, no studies
have examined activities of LNK in solid tumors. In this study, we found by in
silico analysis and staining tissue arrays that the levels of LNK expression were
elevated in high-grade ovarian cancer. To test the functional importance of this
observation, LNK was either overexpressed or silenced in several ovarian cancer
cell lines. Remarkably, overexpression of LNK rendered the cells resistant to
death induced by either serum starvation or nutrient deprivation, and generated
larger tumors using a murine xenograft model. In contrast, silencing of LNK
decreased ovarian cancer cell growth in vitro and in vivo. Western blot studies
indicated that overexpression of LNK upregulated and extended the transduction of
the mitogenic signal, whereas silencing of LNK produced the opposite effects.
Furthermore, forced expression of LNK reduced cell size, inhibited cell migration
and markedly enhanced cell adhesion. Liquid chromatography-mass spectroscopy
identified 14-3-3 as one of the LNK-binding partners. Our results suggest that in
contrast to the findings in hematologic malignancies, the adaptor protein LNK
acts as a positive signal transduction modulator in ovarian cancers.
|14-3-3 Proteins/*metabolism
[MESH]
|Adaptor Proteins, Signal Transducing
[MESH]
|Animals
[MESH]
|Cell Adhesion/physiology
[MESH]
|Cell Line, Tumor
[MESH]
|Cell Movement/physiology
[MESH]
|Cell Proliferation/*physiology
[MESH]
|Cell Size
[MESH]
|Female
[MESH]
|Humans
[MESH]
|Intracellular Signaling Peptides and Proteins
[MESH]
|Mice
[MESH]
|Mice, Inbred NOD
[MESH]
|Mice, SCID
[MESH]
|Mitogen-Activated Protein Kinases/metabolism
[MESH]
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free
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