Transcription repressor slug promotes carcinoma invasion and predicts outcome of patients with lung adenocarcinoma.
OBJECTIVE
In a previous genome-wide gene expression profiling analysis using an invasion cancer cell lines model, we have identified Slug as selectively overexpressed in the highly invasive cancer cells. Here, we investigated the clinical significance of Slug in lung adenocarcinoma and the role of Slug in the process of cancer cell invasion and metastasis.


METHODS
Real-time quantitative reverse transcription-PCR was used to investigate Slug mRNA in surgically resected lung adenocarcinoma of 54 patients and its correlation with survival. We overexpressed Slug in a lung adenocarcinoma cell line with very low Slug levels and investigated the in vitro and in vivo effects of Slug expression.


RESULTS
High expression of Slug mRNA in lung cancer tissue was significantly associated with postoperative relapse (P = 0.03) and shorter patient survival (P < 0.001). The overexpression of Slug enhanced xenograft tumor growth and increased microvessel counts in angiogenesis assay. Both inducible and constitutive overexpression of Slug suppressed the expression of E-cadherin and increased the in vitro invasive ability. Zymography revealed increased matrix metalloproteinase-2 activity in Slug overexpressed cells. ELISA, reverse transcription-PCR, and immunohistochemistry confirmed the increase of matrix metalloproteinase-2 proteins and mRNA in Slug overexpressed cells and xenograft tumors.


CONCLUSIONS
Slug expression can predict the clinical outcome of lung adenocarcinoma patients. Slug is a novel invasion-promoting gene in lung adenocarcinoma.
Shih
Jin-Yuan
JY
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Tsai
Meng-Feng
MF
Chang
Tzu-Hua
TH
Chang
Yih-Leong
YL
Yuan
Ang
A
Yu
Chong-Jen
CJ
Lin
Shin-Bey
SB
Liou
Geou-Yarh
GY
Lee
Meng-Larn
ML
Chen
Jeremy J W
JJ
Hong
Tse-Ming
TM
Yang
Shuenn-Chen
SC
Su
Jen-Liang
JL
Lee
Yung-Chie
YC
Yang
Pan-Chyr
PC
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D000368:Aged; D000818:Animals; D015152:Blotting, Northern; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D014162:Transfection; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
D015820:Cadherins; D012333:RNA, Messenger; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D020778:Matrix Metalloproteinase 2