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 RYJ; Tang K; Koeffler HP
Oncogene 2015[Mar]; 34 (11): 1463-74 PMID24704825show ga
LNK (SH2B3) is an adaptor protein studied extensively in normal and malignant hematopoietic cells. In these cells, it down-regulates 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 the LNK produced the opposite effects. Furthermore, forced expression of LNK reduced cell size, inhibited cell migration and markedly enhanced cell adhesion. LC-MS 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.
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Oncogene 2015 ; 34 (11): 1463-74
