Expression features of SOX9 associate with tumor progression and poor prognosis of hepatocellular carcinoma

Diagnostic Pathology

Jingmin Zhao⁵  Hanwei Li⁵  Jing Zhang²  Haiyan Zhu³  Lin Zou³  Ruiyun Peng²  Ting Sun⁴  Lu Xiong²  Xiaodong Guo¹ 

[1] 302 Hospital of PLA, Beijing, 100039, China;Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, 100850, China;PLA GENERAL HOSPITAL, Beijing, 100853, China;Navy General Hospital of PLA, Beijing, 100049, China;Postgraduate Medical School of PLA, Beijing, 100853, China

关键词: Prognosis;    Tumor progression;    Expression;    SOX9;    Hepatocellular carcinoma;   

Others  :  808107
DOI  :  10.1186/1746-1596-7-44

 received in 2012-03-10, accepted in 2012-04-19,  发布年份 2012

【 摘 要 】

Background

SOX9 as a member of the SOX (SRY [sex determining region Y] box) gene superfamily has been previously demonstrated to be a proto-oncogene in a variety of malignancies. However, the clinical significance of SOX9 expression in hepatocellular carcinoma (HCC) remains unclear. The aim of this study was to investigate the expression of SOX9 in HCC and determine its correlation with tumor progression and prognosis.

Methods

One-hundred and thirty HCC patients who had undergone curative liver resection were selected and immunohistochemistry, Western blotting, and quantitative real time polymerase chain reaction (Q-PCR) were performed to analyze SOX9 expression in the respective tumors.

Results

Immunohistochemistry, Western blotting, and Q-PCR consistently confirmed SOX9 overexpression in HCC tissues compared with their adjacent nonneoplastic tissues (P ≪ 0.01). Additionally, immunostaining showed more SOX9 positive cells in the higher tumor stage (T3 ~ 4) and tumor grade (G3) than in the lower tumor stage (T1 ~ 2, P = 0.03) and tumor grade (G1 ~ 2, P = 0.01), respectively. Moreover, HCC patients with high SOX9 expression were significantly associated with lower 5-year overall survival (P ≪ 0.01) and lower 5-year disease-free survival (P ≪ 0.01), respectively. The Cox proportional hazards model further showed that SOX9 over-expression was an independent poor prognostic factor for both 5-year disease-free survival (hazards ratio [HR] = 2.621, 95% confidence interval[CI] = 1.548-5.829, P = 0.01) and 5-year overall survival (HR = 3.825, CI = 1.638-7.612, P = 0.003) in HCC.

Conclusion

Our data suggest for the first time that the overexpression of SOX9 protein in HCC tissues is of predictive value on tumor progression and poor prognosis.

Virtual slides

The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9029740396926377 webcite.

【 授权许可】

   
2012 Guo et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Li J, Jiang X: Loss of runt-related transcription factor 3 expression associated with human hepatocellular carcinoma progression and prognosis. Asian Pac J Cancer Prev 2011, 12:2285-2290.
• [2]Zhong C, Wei W, Su XK, Li HD, Xu FB, Guo RP: Serum and tissue vascular endothelial growth factor predicts prognosis in hepatocellular carcinoma patients after partial liver resection. Hepatogastroenterology 2012, 59:93-97.
• [3]Lin W, Chen YL, Jiang L, Chen JK: Reduced expression of chemerin is associated with a poor prognosis and a lowed infiltration of both dendritic cells and natural killer cells in human hepatocellular carcinoma. Clin Lab 2011, 57:879-885.
• [4]Dettmer M, Itin P, Miny P, Gandhi M, Cathomas G, Willi N: Giant ectopic liver, hepatocellular carcinoma and pachydermia-a rare genetic syndrome? Diagn Pathol 2011, 6:75. BioMed Central Full Text
• [5]Foster JW, Dominguez-Steglich MA, Guioli S, Kwok C, Weller PA, Stevanović M, Weissenbach J, Mansour S, Young ID, Goodfellow PN: Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature 1994, 372:525-530.
• [6]Wagner T, Wirth J, Meyer J, Zabel B, Held M, Zimmer J, Pasantes J, Bricarelli FD, Keutel J, Hustert E, Wolf U, Tommerup N, Schempp W, Scherer G: Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell 1994, 79:1111-1120.
• [7]Bi W, Huang W, Whitworth DJ, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B: Haploinsufficiency of SOX9 results in defective cartilage primordia and premature skeletal mineralization. Proc Natl Acad Sci USA 2001, 98:6698-6703.
• [8]Hersmus R, Kalfa N, de Leeuw B, Stoop H, Oosterhuis JW, de Krijger R, Wolffenbuttel KP, Drop SL, Veitia RA, Fellous M, Jaubert F, Looijenga LH: FOXL2 and SOX9 as parameters of female and male gonadal differentiation in patients with various forms of disorders of sex development (DSD). J Pathol 2008, 215:31-38.
• [9]Knower KC, Kelly S, Ludbrook LM, Bagheri-Fam S, Sim H, Bernard P, Sekido R, Lovell-Badge R, Harley VR: Failure of SOX9 regulation in 46XY disorders of sex development with SRY, SOX9 and SF1 mutations. PLoS One 2011, 6:e17751.
• [10]Ling S, Chang X, Schultz L, Lee TK, Chaux A, Marchionni L, Netto GJ, Sidransky D, Berman DM: An EGFR-ERK-SOX9 signaling cascade links urothelial development and regeneration to cancer. Cancer Res 2011, 71:3812-3821.
• [11]Chakravarty G, Moroz K, Makridakis NM, Lloyd SA, Galvez SE, Canavello PR, Lacey MR, Agrawal K, Mondal D: Prognostic significance of cytoplasmic SOX9 in invasive ductal carcinoma and metastatic breast cancer. Exp Biol Med (Maywood) 2011, 236:145-155.
• [12]Krahl D, Sellheyer K: Basal cell carcinoma and pilomatrixoma mirror human follicular embryogenesis as reflected by their differential expression patterns of SOX9 and β-catenin. Br J Dermatol 2010, 162:1294-1301.
• [13]Afonja O, Raaka BM, Huang A, Das S, Zhao X, Helmer E, Juste D, Samuels HH: RAR agonists stimulate SOX9 gene expression in breast cancer cell lines: evidence for a role in retinoid-mediated growth inhibition. Oncogene 2002, 21:7850-7860.
• [14]Wang H, Leav I, Ibaragi S, Wegner M, Hu GF, Lu ML, Balk SP, Yuan X: SOX9 is expressed in human fetal prostate epithelium and enhances prostate cancer invasion. Cancer Res 2008, 68:1625-1630.
• [15]Aleman A, Adrien L, Lopez-Serra L, Cordon-Cardo C, Esteller M, Belbin TJ, Sanchez-Carbayo M: Identification of DNA hypermethylation of SOX9 in association with bladder cancer progression using CpG microarrays. Br J Cancer 2008, 98:466-473.
• [16]Malki S, Bibeau F, Notarnicola C, Roques S, Berta P, Poulat F, Boizet-Bonhoure B: Expression and biological role of the prostaglandin D synthase/SOX9 pathway in human ovarian cancer cells. Cancer Lett 2007, 255:182-193.
• [17]GUO XD XIONGL, ZOU L, ZHAO JM: Upregulation of bone morphogenetic protein 4 is associated with poor prognosis in patients with hepatocellular carcinoma. Pathology & Oncology Research In press
• [18]Schmilovitz-Weiss H, Tobar A, Halpern M, Levy I, Shabtai E, Ben-Ari Z: Tissue expression of squamous cellular carcinoma antigen and Ki67 in hepatocellular carcinoma-correlation with prognosis: A historical prospective study. Diagn Pathol 2011, 6:121. BioMed Central Full Text
• [19]Hong H, Patonay B, Finley J: Unusual reticulin staining pattern in well-differentiated hepatocellular carcinoma. Diagn Pathol 2011, 6:15. BioMed Central Full Text
• [20]Müller P, Crofts JD, Newman BS, Bridgewater LC, Lin CY, Gustafsson JA, Ström A: SOX9 mediates the retinoic acid-induced HES-1 gene expression in human breast cancer cells. Breast Cancer Res Treat 2010, 120:317-326.
• [21]Lü B, Fang Y, Xu J, Wang L, Xu F, Xu E, Huang Q, Lai M: Analysis of SOX9 expression in colorectal cancer. Am J Clin Pathol 2008, 130:897-904.
• [22]Xu MZ, Yao TJ, Lee NP, Ng IO, Chan YT, Zender L, Lowe SW, Poon RT, Luk JM: Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma. Cancer 2009, 115:4576-4585.
• [23]Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 2001, 25:402-408.
• [24]Kent J, Wheatley SC, Andrews JE, Sinclair AH, Koopman P: A male specific role for SOX9 in vertebrate sex determination. Development 1996, 122:2813-2822.
• [25]Spokony RF, Aoki Y, Saint-Germain N, Magner-Fink E, Saint-Jeannet JP: The transcription factor SOX9 is required for cranial neural crest development in Xenopus. Development 2002, 129:421-432.
• [26]Blache P, van de Wetering M, Duluc I, Domon C, Berta P, Freund JN, Clevers H, Jay P: SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 gene. J Cell Biol 2004, 166:37-47.
• [27]Liang B, Cotter MM, Chen D, Hernandez CJ, Zhou G: Ectopic Expression of SOX9 in Osteoblasts Alters Bone Mechanical Properties. Calcif Tissue Int 2012, 90:76-89.
• [28]Jiang SS, Fang WT, Hou YH, Huang SF, Yen BL, Chang JL, Li SM, Liu HP, Liu YL, Huang CT, Li YW, Jang TH, Chan SH, Yang SJ, Hsiung CA, Wu CW, Wang LH, Chang IS: Upregulation of SOX9 in lung adenocarcinoma and its involvement in the regulation of cell growth and tumorigenicity. Clin Cancer Res 2010, 16:4363-4373.
• [29]Sashikawa Kimura M, Mutoh H, Sugano K: SOX9 is expressed in normal stomach, intestinal metaplasia, and gastric carcinoma in humans. J Gastroenterol 2011, 46:1292-1299.
• [30]Liu JN, Shang Guan YM, Qi YZ, Wang HB, Zhang TG, Zhou CJ: The evaluation of SOX9 expression and its relationship with carcinoembryonic antigen-related cell adhesion molecule 1 in gastric neoplastic and nonneoplastic lesions. Ann Diagn Pathol 2011. In press
• [31]Jay P, Berta P, Blache P: Expression of the carcinoembryonic antigen gene is inhibited by SOX9 in human colon carcinoma cells. Cancer Res 2005, 65:2193-2198.