Down-regulation of growth arrest DNA damage-inducible gene 45beta expression is associated with human hepatocellular carcinoma.
In this study, we describe the growth arrest DNA damage-inducible gene 45beta (GADD45beta), whose expression was significantly down-regulated in the hepatocellular carcinoma (HCC) microarray study and confirmed by Northern blot analysis. The results suggested that expression of GADD45beta was decreased in human liver cancer cell lines HepG2 and Hep3B, but not in normal human embryonic liver cell line CL-48 or normal liver tissue. Histochemistry study and real-time PCR further confirmed that GADD45beta staining in HCC was significantly decreased when compared to surrounding non-neoplastic liver tissue. In further studies of multiple human cancer tissues, GADD45beta strongly stained tissues such as colon cancer, breast cancer, prostate cancer, squamous cell cancer, lymphoma, and leiomyosarcoma, suggesting that the decreased expression of GADD45beta is specific to HCC. Eighty-five cases of primary HCC were further examined by immunohistochemistry and statistical analyses demonstrated that HCC scored lower than matched non-neoplastic liver tissues consistently and significantly. No staining occurred in 12.94% of HCC cases (score = 0, n = 11); 42.35% had weak staining (score = 1, n = 36); 27.06% had moderate staining (score = 2, n = 23); and 17.65% had staining as strong as normal tissue (score = 3, n = 15). Overall, surrounding non-neoplastic liver tissue was highly positive for GADD45beta compared to adjacent neoplastic liver tissues (P < 0.01). We further observed that down-regulation of GADD45beta expression was strongly correlated with differentiation (P < 0.01) and high nuclear grade (P < 0.01). Moreover, we found that expression of GADD45beta was inversely correlated to the presence of mutant p53 in HCC tissue (P < 0.05). Thus, the results of our study suggest that GADD45beta, which is down-regulated in most cases of HCC, remains an ideal candidate for development as a molecular marker in the diagnosis of HCC and as a potential therapeutic target.
Qiu
Weihua
W
Department of Medical Oncology and Therapeutic Research, Gastrointestinal Disease, Pathology, and Biostatistics, City of Hope National Medical Center, Duarte, California 91010, USA.
David
Donald
D
Zhou
Bingsen
B
Chu
Peiguo G
PG
Zhang
Bohe
B
Wu
Mengchao
M
Xiao
Jiacheng
J
Han
Tianquan
T
Zhu
Zhenggang
Z
Wang
Tianxiang
T
Liu
Xiyong
X
Lopez
Richard
R
Frankel
Paul
P
Jong
Ambrose
A
Yen
Yun
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000943:Antigens, Differentiation / Q000235:genetics* / Q000378:metabolism; D015152:Blotting, Northern; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014407:Tumor Cells, Cultured; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D012333:RNA, Messenger; C086470:GADD45B protein, human; D000097642:GADD45 Proteins