Down-Regulation of Growth Arrest DNA Damage-Inducible Gene 45β Expression Is Associated with Human Hepatocellular Carcinoma

Abstract

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.

Overexpression of the Transcription Factor MEF2D in Hepatocellular Carcinoma Sustains Malignant Character by Suppressing G2–M Transition Genes

“…CDKN1A (p21, Cip1) upregulation is also required for G 2 -M arrest induced by a variety of drugs (38). GADD45A is known to allow HepG2 cells to undergo G 2 -M arrest (39), whereas decreased GADD45B expression in human hepatocellular carcinoma tissues is significantly associated with histologic grading of tumors (40). Collectively, our data indicated that MEF2D promoted cell growth by downregulating G 2 -M transition-inhibiting genes.…”

Over-expression of fibroblast growth factor receptor 3 in human hepatocellular carcinoma

“…The partial result of microarray has been published in our previous study [6] . Among the 59 genes whose expression levels were most significantly changed, 30 over-expressed genes and 29 under-expressed genes were identified in HCC.…”

“…No HCC cells were contaminated in non-neoplastic liver tissues which were reassured before further approach. RNA isolation, cRNA preparation and microarray hybridization were performed as described previously [6] . The microarray format, scanning and data analysis were performed at the Microarray Core Facility, Children's Hospital, Los Angeles,USA.…”

“…This technology has been applied successfully in the identification of key genes in neoplastic transformation and as a diagnosis tool in molecular pathology [4,5] . In a previous study, a DNA microarray is used to compare the gene expression profile of HCC tissues with that of matched non-neoplastic tissue [6] . In this study, we focused on the expression change of transcription and translation-related genes in microarray gene profile.…”

Induction of DNA Damage-Inducible Gene GADD45β Contributes to Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma Cells

“…GADD45 family proteins are frequently underexpressed in various types of cancers, including HCC (9,14,15). GADD45 family proteins are also important mediators of genotoxic stress-induced and transforming growth factor-β (TGF-β)-induced apoptosis (16)(17)(18).…”