p75 neurotrophin receptor suppresses the proliferation of human gastric cancer cells.
Identifying an effective therapeutic target is pivotal in the treatment of gastric cancer. In this study, we investigated the expression of p75 neurotrophin receptor (p75NTR) in gastric cancer and the impact of its alteration on tumor growth. p75NTR expression was absent or significantly decreased in 212 cases of gastric cancers compared with the normal gastric mucosa (P < .05). Moreover, p75NTR expression was also lost or significantly decreased in various human gastric cancer cell lines. p75NTR inhibited in vitro growth activities and caused dramatic attenuation of tumor growth in animal models by induction of cell cycle arrest. Upregulation of p75NTR led to downregulation of cyclin A, cyclin D1, cyclin E, cyclin-dependent kinase 2, p-Rb, and PCNA, but to upregulation of Rb and p27 expressions. Conversely, downregulating p75NTR with specific siRNA yielded inverse results. The rescue of tumor cells from cell cycle progression by a death domain-deleted dominant-negative antagonist of p75NTR (Deltap75NTR) showed that the death domain transduced antiproliferative activity in a ligand-independent manner and further demonstrated the inhibitive effect of p75NTR on growth in gastric cancer. Therefore, we provided evidence that p75NTR was a potential tumor suppressor and may be used as a therapeutic target for gastric cancer.
Jin
Haifeng
H
State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi Province 710032, China.
Pan
Yanglin
Y
Zhao
Lina
L
Zhai
Huihong
H
Li
Xiaohua
X
Sun
Li
L
He
Lijie
L
Chen
Yu
Y
Hong
Liu
L
Du
Yulei
Y
Fan
Daiming
D
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D019925:Cyclin A / Q000378:metabolism; D056750:Cyclin A1; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020800:Receptor, Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020812:Receptor, trkC; D016160:Retinoblastoma Protein / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015996:Survival Rate; D014407:Tumor Cells, Cultured
C503745:CCNA1 protein, human; D019925:Cyclin A; D056750:Cyclin A1; D019927:Cyclin E; D018809:Proliferating Cell Nuclear Antigen; D034741:RNA, Small Interfering; D020800:Receptor, Nerve Growth Factor; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D020812:Receptor, trkC; D051357:Cyclin-Dependent Kinase 2