Down-regulation of growth arrest DNA damage-inducible gene 45β expression is associated with human hepatocellular carcinoma

Weihua Qiu, Donald David, Bingsen Zhou, Peiguo G. Chu, Bohe Zhang, Mengchao Wu, Jiacheng Xiao, Tianquan Han, Zhenggang Zhu, Tianxiang Wang, Xiyong Liu, Richard Lopez, Paul Frankel, Ambrose Jong, Yun Yen

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Abstract

In this study, we describe the growth arrest DNA damage-inducible gene 45β (GADD45β), 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 GADD45β was decreased in human liver cancer cell lines HepG2 and Hep3β, but not in normal human embryonic liver cell line CL-48 or normal liver tissue. Histochemistry study and realtime PCR further confirmed that GADD45β staining in HCC was significantly decreased when compared to surrounding non-neoplastic liver tissue. In further studies of multiple human cancer tissues, GADD45β strongly stained tissues such as colon cancer, breast cancer, prostate cancer, squamous cell cancer, lymphoma, and leiomyosarcoma, suggesting that the decreased expression of GADD45β 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 GADD45β compared to adjacent neoplastic liver tissues (P < 0.01). We further observed that down-regulation of GADD45β expression was strongly correlated with differentiation (P < 0.01) and high nuclear grade (P < 0.01). Moreover, we found that expression of GADD45β was inversely correlated to the presence of mutant p53 in HCC tissue (P < 0.05). Thus, the results of our study suggest that GADD45β, 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.

Original languageEnglish
Pages (from-to)1961-1974
Number of pages14
JournalAmerican Journal of Pathology
Volume162
Issue number6
DOIs
Publication statusPublished - Jun 1 2003
Externally publishedYes

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DNA Damage
Hepatocellular Carcinoma
Down-Regulation
Gene Expression
Growth
Genes
Staining and Labeling
Liver
Prostatic Neoplasms
Breast Neoplasms
Cell Line
Squamous Cell Neoplasms
Leiomyosarcoma
Liver Neoplasms
Northern Blotting
Colonic Neoplasms
Lymphoma
Immunohistochemistry
Polymerase Chain Reaction
Neoplasms

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Down-regulation of growth arrest DNA damage-inducible gene 45β expression is associated with human hepatocellular carcinoma. / Qiu, Weihua; David, Donald; Zhou, Bingsen; Chu, Peiguo G.; Zhang, Bohe; Wu, Mengchao; Xiao, Jiacheng; Han, Tianquan; Zhu, Zhenggang; Wang, Tianxiang; Liu, Xiyong; Lopez, Richard; Frankel, Paul; Jong, Ambrose; Yen, Yun.

In: American Journal of Pathology, Vol. 162, No. 6, 01.06.2003, p. 1961-1974.

Research output: Contribution to journalArticle

Qiu, W, David, D, Zhou, B, Chu, PG, Zhang, B, Wu, M, Xiao, J, Han, T, Zhu, Z, Wang, T, Liu, X, Lopez, R, Frankel, P, Jong, A & Yen, Y 2003, 'Down-regulation of growth arrest DNA damage-inducible gene 45β expression is associated with human hepatocellular carcinoma', American Journal of Pathology, vol. 162, no. 6, pp. 1961-1974. https://doi.org/10.1016/S0002-9440(10)64329-5
Qiu, Weihua ; David, Donald ; Zhou, Bingsen ; Chu, Peiguo G. ; Zhang, Bohe ; Wu, Mengchao ; Xiao, Jiacheng ; Han, Tianquan ; Zhu, Zhenggang ; Wang, Tianxiang ; Liu, Xiyong ; Lopez, Richard ; Frankel, Paul ; Jong, Ambrose ; Yen, Yun. / Down-regulation of growth arrest DNA damage-inducible gene 45β expression is associated with human hepatocellular carcinoma. In: American Journal of Pathology. 2003 ; Vol. 162, No. 6. pp. 1961-1974.
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abstract = "In this study, we describe the growth arrest DNA damage-inducible gene 45β (GADD45β), 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 GADD45β was decreased in human liver cancer cell lines HepG2 and Hep3β, but not in normal human embryonic liver cell line CL-48 or normal liver tissue. Histochemistry study and realtime PCR further confirmed that GADD45β staining in HCC was significantly decreased when compared to surrounding non-neoplastic liver tissue. In further studies of multiple human cancer tissues, GADD45β strongly stained tissues such as colon cancer, breast cancer, prostate cancer, squamous cell cancer, lymphoma, and leiomyosarcoma, suggesting that the decreased expression of GADD45β 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 GADD45β compared to adjacent neoplastic liver tissues (P < 0.01). We further observed that down-regulation of GADD45β expression was strongly correlated with differentiation (P < 0.01) and high nuclear grade (P < 0.01). Moreover, we found that expression of GADD45β was inversely correlated to the presence of mutant p53 in HCC tissue (P < 0.05). Thus, the results of our study suggest that GADD45β, 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.",
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AU - Zhang, Bohe

AU - Wu, Mengchao

AU - Xiao, Jiacheng

AU - Han, Tianquan

AU - Zhu, Zhenggang

AU - Wang, Tianxiang

AU - Liu, Xiyong

AU - Lopez, Richard

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AU - Jong, Ambrose

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