Suppression of anoikis by SKP2 amplification and overexpression promotes metastasis of esophageal squamous cell carcinoma.
The gene of SKP2, located on chromosome 5p13, plays a critical role in cell cycle progression, especially at the G(1)-S transition, putatively through its control of several cell cycle regulator proteins including p27(kip1), p21(cip1), p57(kip2), p130, cyclin E, and c-Myc. Previous studies in this laboratory revealed that gain of chromosome 5p was often seen in esophageal squamous cell carcinoma (ESCC). In the present study, we examined the amplification status and expression level of SKP2 in ESCC and investigated its clinicopathologic significance. Amplification and elevated expression of SKP2 correlated significantly with tumor stage and positive lymph node metastasis (P < 0.05). The SKP2 protein expression level as determined by immunohistochemical staining showed a significant inverse correlation with p27 protein. In vivo assay showed that inhibition of SKP2 expression also decreased tumor growth and lung metastasis of ESCC cells. At the molecular level, knockdown of SKP2 by RNA interference inhibited cell migration and invasion ability. Knockdown of SKP2 expression sensitized cancer cells to anoikis, and a wobble mutant of SKP2 that is resistant to SKP2 small interfering RNA can rescue this effect. Expression level of pAkt decreased after SKP2 knockdown. Treatment of cells with phosphoinositidyl 3-kinase inhibitor (LY294002) and constitutively activator (insulin-like growth factor I) had significant effects on the anoikis of SKP2 RNA interference cells. These results show for the first time that SKP2 is amplified and overexpressed in ESCC. Elevated expression of SKP2 protected cancer cells from anoikis, and this effect was mediated, at least in part, by the phosphoinositidyl 3-kinase-Akt pathway.
Wang
Xiao-Chun
XC
State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, P.O. Box 2258, Beijing 100021, China.
Wu
Yu-Peng
YP
Ye
Bo
B
Lin
De-Chen
DC
Feng
Yan-Bin
YB
Zhang
Zi-Qiang
ZQ
Xu
Xin
X
Han
Ya-Ling
YL
Cai
Yan
Y
Dong
Jin-Tang
JT
Zhan
Qi-Min
QM
Wu
Min
M
Wang
Ming-Rong
MR
D023102:Anoikis / Q000235:genetics*; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D002465:Cell Movement / Q000235:genetics; D017931:DNA Primers; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D005784:Gene Amplification; D006801:Humans; D008207:Lymphatic Metastasis / Q000235:genetics*; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010957:Plasmids; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D034622:RNA Interference; D012334:RNA, Neoplasm / Q000235:genetics; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics*
D017931:DNA Primers; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012334:RNA, Neoplasm; D044786:S-Phase Kinase-Associated Proteins; D051057:Proto-Oncogene Proteins c-akt