Abnormal expression of GADD45B in human colorectal carcinoma

Journal of Translational Medicine

Xiang Du²  Xiaoyan Zhou³  Cong Tan³  Shujuan Ni³  Yiqin Wang³  Ping Wei³  Yayun Chi⁴  Dali Li³  Xiuying Xiao¹  Lisha Wang³ 

[1] Department of Oncology, Shanghai Xuhui District Center Hospital, Shanghai, 200031, China;Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China;Institute of Pathology, Fudan University, Shanghai, 200032, China;Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

关键词: Relapse;    Carcinogenesis;    GADD45B;    Colorectal carcinoma;   

Others  :  829090
DOI  :  10.1186/1479-5876-10-215

 received in 2012-07-11, accepted in 2012-10-18,  发布年份 2012

【 摘 要 】

Background

GADD45B is a member of the growth arrest DNA damage-inducible gene family associated with cell growth control, apoptosis, and DNA damage repair response. The aim of this study is to detect the role of GADD45B in colorectal carcinoma (CRC); the area not studied in depth to date.

Methods

The mRNA and protein levels of GADD45B were examined by Real-Time quantitative PCR (RT-qPCR) and immunohistochemistry (IHC) in CRC tissues and adjacent noncancerous tissues (ANCT). Over-expression plasmids and SiRNA were used to regulate GADD45B expression in CRC cell lines in vitro and flow cytometry and Western blotting were used to detect apoptotic changes.

Results

The mRNA and protein levels of GADD45B were significantly higher in CRC tissues than those in ANCT (P<0.05). Up-regulation of GADD45B was also correlated with relapse and death of CRC patients (P<0.05). The Kaplan-Meier survival curves indicated that disease-free survival (DFS) was significantly worse in CRC patients who showed GADD45B overexpression. A Cox multivariate analysis revealed that GADD45B overexpression and TNM stage were significant factors affecting patients’ survival. On the other hand, as a tumor suppressor gene, GADD45B amplified from normal colorectal tissues could induce apoptosis in CRC cell lines and may be associated with the p53-mediated apoptotic pathways.

Conclusion

GADD45B, a tumor suppressor gene potentially through the p53-mediated apoptotic pathways, is paradoxically overexpressed in CRC and as such may play an unappreciated role in tumorigenesis. The exact mechanism of GADD45B inactivation and overexpression requires further investigation. GADD45B could be a potential therapeutic target for CRC treatment in future.

【 授权许可】

   
2012 Wang et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Center MM, Jemal A, Ward E: International trends in colorectal cancer incidence rates. Cancer Epidemiol Biomarkers Prev 2009, 18:1688-1694.
• [2]Harpaz N, Polydorides AD: Colorectal dysplasia in chronic inflammatory bowel disease: pathology, clinical implications, and pathogenesis. Arch Pathol Lab Med 2010, 134:876-895.
• [3]Campos FG, Logullo WA, Kiss DR, Waitzberg DL, Habr-Gama A, Gama-Rodrigues J: Diet and colorectal cancer: current evidence for etiology and prevention. Nutr Hosp 2005, 20:18-25.
• [4]Liebermann DA, Hoffman B: Myeloid differentiation (MyD)/growth arrest DNA damage (GADD) genes in tumor suppression, immunity and inflammation. Leukemia 2002, 16:527-541.
• [5]Liebermann DA, Hoffman B: Myeloid differentiation (MyD) primary response genes in hematopoiesis. Blood Cells Mol Dis 2003, 31:213-228.
• [6]Michaelis KA, Knox AJ, Xu M, Kiseljak-Vassiliades K, Edwards MG, Geraci M, Kleinschmidt-DeMasters BK, Lillehei KO, Wierman ME: Identification of growth arrest and DNA-damage-inducible gene beta (GADD45beta) as a novel tumor suppressor in pituitary gonadotrope tumors. Endocrinology 2011, 152:3603-3613.
• [7]Ou DL, Shen YC, Yu SL, Chen KF, Yeh PY, Fan HH, Feng WC, Wang CT, Lin LI, Hsu C, Cheng AL: Induction of DNA damage-inducible gene GADD45beta contributes to sorafenib-induced apoptosis in hepatocellular carcinoma cells. Cancer Res 2010, 70:9309-9318.
• [8]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: Down-regulation of growth arrest DNA damage-inducible gene 45beta expression is associated with human hepatocellular carcinoma. Am J Pathol 2003, 162:1961-1974.
• [9]Lin B, Utleg AG, Gravdal K, White JT, Halvorsen OJ, Lu W, True LD, Vessella R, Lange PH, Nelson PS, Hood L, Kalland KH, Akslen LA: WDR19 expression is increased in prostate cancer compared with normal cells, but low-intensity expression in cancers is associated with shorter time to biochemical failures and local recurrence. Clin Cancer Res 2008, 14:1397-1406.
• [10]Halvorsen OJ, Rostad K, Oyan AM, Puntervoll H, Bo TH, Stordrange L, Olsen S, Haukaas SA, Hood L, Jonassen I, Kalland KH, Akslen LA: Increased expression of SIM2-s protein is a novel marker of aggressive prostate cancer. Clin Cancer Res 2007, 13:892-897.
• [11]Bustin SA: Absolute quantification of mRNA using real-time reverse transcription polymerase chain reaction assays. J Mol Endocrinol 2000, 25:169-193.
• [12]Skirnisdottir I, Sorbe B, Seidal T: P53, bcl-2, and bax: their relationship and effect on prognosis in early stage epithelial ovarian carcinoma. Int J Gynecol Cancer 2001, 11:147-158.
• [13]Liu X, Cai H, Huang H, Long Z, Shi Y, Wang Y: The prognostic significance of apoptosis-related biological markers in Chinese gastric cancer patients. PLoS One 2011, 6:e29670.
• [14]Czabotar PE, Lessene G: Bcl-2 family proteins as therapeutic targets. Curr Pharm Des 2010, 16:3132-3148.
• [15]Chen W, Gao N, Shen Y, Cen JN: Hypermethylation downregulates Runx3 gene expression and its restoration suppresses gastric epithelial cell growth by inducing p27 and caspase3 in human gastric cancer. J Gastroenterol Hepatol 2010, 25:823-831.
• [16]Fearon ER: Molecular genetics of colorectal cancer. Annu Rev Pathol 2011, 6:479-507.
• [17]O’Connell MJ, Lavery I, Yothers G, Paik S, Clark-Langone KM, Lopatin M, Watson D, Baehner FL, Shak S, Baker J, Cowens JW, Wolmark N: Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin. J Clin Oncol 2010, 28:3937-3944.
• [18]Zhang D, Salto-Tellez M, Putti TC, Do E, Koay ES: Reliability of tissue microarrays in detecting protein expression and gene amplification in breast cancer. Mod Pathol 2003, 16:79-84.
• [19]Schmidt LH, Biesterfeld S, Kummel A, Faldum A, Sebastian M, Taube C, Buhll R, Wiewrodt R: Tissue microarrays are reliable tools for the clinicopathological characterization of lung cancer tissue. Anticancer Res 2009, 29:201-209.
• [20]Takekawa M, Saito H: A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Cell 1998, 95:521-530.
• [21]Yang Z, Song L, Huang C: Gadd45 proteins as critical signal transducers linking NF-kappaB to MAPK cascades. Curr Cancer Drug Targets 2009, 9:915-930.
• [22]Liebermann DA, Tront JS, Sha X, Mukherjee K, Mohamed-Hadley A, Hoffman B: Gadd45 stress sensors in malignancy and leukemia. Crit Rev Oncog 2011, 16:129-140.
• [23]Ju S, Zhu Y, Liu L, Dai S, Li C, Chen E, He Y, Zhang X, Lu B: Gadd45b and Gadd45g are important for anti-tumor immune responses. Eur J Immunol 2009, 39:3010-3018.
• [24]Liebermann DA, Hoffman B: Gadd45 in the response of hematopoietic cells to genotoxic stress. Blood Cells Mol Dis 2007, 39:329-335.
• [25]Higgs MR, Lerat H, Pawlotsky JM: Downregulation of Gadd45beta expression by hepatitis C virus leads to defective cell cycle arrest. Cancer Res 2010, 70:4901-4911.
• [26]Jiang C, Zhou B, Fan K, Heung E, Xue L, Liu X, Kirschbaum M, Yen Y: A sequential treatment of depsipeptide followed by 5-azacytidine enhances Gadd45beta expression in hepatocellular carcinoma cells. Anticancer Res 2007, 27:3783-3789.
• [27]Tenta R, Katopodis H, Chatziioannou A, Pilalis E, Calvo E, Luu-The V, Labrie F, Kolisis F, Koutsilieris M: Microarray analysis of survival pathways in human PC-3 prostate cancer cells. CANCER GENOMICS PROTEOMICS 2007, 4:309-318.
• [28]Hu Y, Sun H, Drake J, Kittrell F, Abba MC, Deng L, Gaddis S, Sahin A, Baggerly K, Medina D, Aldaz CM: From mice to humans: identification of commonly deregulated genes in mammary cancer via comparative SAGE studies. Cancer Res 2004, 64:7748-7755.
• [29]Gingras D, Beliveau R: Colorectal cancer prevention through dietary and lifestyle modifications. Cancer Microenviron 2011, 4:133-139.
• [30]Abbass K, Gul W, Beck G, Markert R, Akram S: Association of Helicobacter pylori infection with the development of colorectal polyps and colorectal carcinoma. South Med J 2011, 104:473-476.
• [31]Uronis JM, Muhlbauer M, Herfarth HH, Rubinas TC, Jones GS, Jobin C: Modulation of the intestinal microbiota alters colitis-associated colorectal cancer susceptibility. PLoS One 2009, 4:e6026.
• [32]Smith ML, Ford JM, Hollander MC, Bortnick RA, Amundson SA, Seo YR, Deng CX, Hanawalt PC, Fornace AJ: p53-mediated DNA repair responses to UV radiation: studies of mouse cells lacking p53, p21, and/or gadd45 genes. Mol Cell Biol 2000, 20:3705-3714.
• [33]Itahana K, Dimri G, Campisi J: Regulation of cellular senescence by p53. Eur J Biochem 2001, 268:2784-2791.
• [34]Hector S, Prehn JH: Apoptosis signaling proteins as prognostic biomarkers in colorectal cancer: a review. Biochim Biophys Acta 2009, 1795:117-129.
• [35]Krajewska M, Kim H, Kim C, Kang H, Welsh K, Matsuzawa S, Tsukamoto M, Thomas RG, Assa-Munt N, Piao Z, Suzuki K, Perucho M, Krajewski S, Reed JC: Analysis of apoptosis protein expression in early-stage colorectal cancer suggests opportunities for new prognostic biomarkers. Clin Cancer Res 2005, 11:5451-5461.
• [36]Nehls O, Okech T, Hsieh CJ, Enzinger T, Sarbia M, Borchard F, Gruenagel HH, Gaco V, Hass HG, Arkenau HT, Hartmann JT, Porschen R, Gregor M, Klump B: Studies on p53, BAX and Bcl-2 protein expression and microsatellite instability in stage III (UICC) colon cancer treated by adjuvant chemotherapy: major prognostic impact of proapoptotic BAX. Br J Cancer 2007, 96:1409-1418.
• [37]Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 2000, 100:57-70.
• [38]Qiu W, Zhou B, Zou H, Liu X, Chu PG, Lopez R, Shih J, Chung C, Yen Y: Hypermethylation of growth arrest DNA damage-inducible gene 45 beta promoter in human hepatocellular carcinoma. Am J Pathol 2004, 165:1689-1699.
• [39]Duerr EM, Mizukami Y, Ng A, Xavier RJ, Kikuchi H, Deshpande V, Warshaw AL, Glickman J, Kulke MH, Chung DC: Defining molecular classifications and targets in gastroenteropancreatic neuroendocrine tumors through DNA microarray analysis. Endocr Relat Cancer 2008, 15:243-256.
• [40]Jamaly S, Khanehkenari MR, Rao R, Patil G, Thakur S, Ramaswamy P, Ajaikumar BS, Sahoo R: Relationship between p53 overexpression, human papillomavirus infection, and lifestyle in Indian patients with head and neck cancers. Tumour Biol 2012, 33:543-550.
• [41]Monteiro LS, Diniz-Freitas M, Garcia-Caballero T, Warnakulasuriya S, Forteza J, Fraga M: Combined cytoplasmic and membranous EGFR and p53 overexpression is a poor prognostic marker in early stage oral squamous cell carcinoma. J Oral Pathol Med 2012, 41:559-567.
• [42]Zhao H, Cui Y, Dupont J, Sun H, Hennighausen L, Yakar S: Overexpression of the tumor suppressor gene phosphatase and tensin homologue partially inhibits wnt-1-induced mammary tumorigenesis. Cancer Res 2005, 65:6864-6873.