Suppression of FHL2 expression induces cell differentiation and inhibits gastric and colon carcinogenesis.
OBJECTIVE
FHL2 (4-1/2 LIM protein 2) is an adapter and modifier in protein interactions that is expressed mainly in the heart and ovary. It functions in a cell type- or promoter-specific manner. The aims of this study were to examine its expression in gastrointestinal cancers and to determine its role in cell differentiation and tumorigenesis.


METHODS
FHL2 expression in cancerous and normal gastrointestinal cells was detected by reverse-transcription polymerase chain reaction, immunoblotting, and immunohistochemistry. The effect of FHL2 suppression by both antisense and siRNA methods on cell differentiation and growth were evaluated in vitro and in vivo.


RESULTS
FHL2 expression was up-regulated in gastrointestinal cancer, compared with matched normal tissues. Stable transfection of gastric cancer cell line, AGS, and colon cancer cell line, Lovo, with antisense FHL2 induced lengthened or shuttle-shape morphologic changes with long or dendritic-like cytoplasmic processes and decreased the nuclear:cytoplasmic ratio. FHL2 antisense induced expressions of carcinoembryonic antigen and E-cadherin and the maturation of F-actin. Furthermore, FHL2 antisense inhibited the transcriptions of some oncogenes including cox-2, survivin, c-jun, and hTERT, and suppressed the promoter activity of activator protein-1 and hTERT. Suppression of FHL2 inhibited serum-dependent, anchorage-dependent and -independent cell growth, and suppressed de novo tumor formation in nude mice xenograft.


CONCLUSIONS
Suppression of FHL2 induces cell differentiation and inhibits tumorigenesis. Antisense or siRNA methods targeting FHL2 is a promising strategy for treatment of gastrointestinal cancers.
Wang
Jide
J
Institute for Digestive Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.
Yang
Yi
Y
Xia
Harry H X
HH
Gu
Qing
Q
Lin
Marie C M
MC
Jiang
Bo
B
Peng
Ying
Y
Li
Guoqing
G
An
Xiaomeng
X
Zhang
Yali
Y
Zhuang
Zehao
Z
Zhang
Zhenshu
Z
Kung
Hsiang Fu
HF
Wong
Benjamin C Y
BC
D000199:Actins / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002272:Carcinoembryonic Antigen / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048430:Cell Shape; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D060850:LIM-Homeodomain Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D016372:RNA, Antisense / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077022:Survivin; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014183:Transplantation, Heterologous; D015854:Up-Regulation
D000199:Actins; C107489:BIRC5 protein, human; D015820:Cadherins; D002272:Carcinoembryonic Antigen; C105987:FHL2 protein, human; D018398:Homeodomain Proteins; D051034:Inhibitor of Apoptosis Proteins; D060850:LIM-Homeodomain Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009124:Muscle Proteins; D009363:Neoplasm Proteins; D016755:Proto-Oncogene Proteins c-jun; D016372:RNA, Antisense; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000077022:Survivin; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C509186:TERT protein, human; D019098:Telomerase