Prognostic value of hedgehog signal component expressions in hepatoblastoma patients

European Journal of Medical Research

Chun-Bao Guo¹  Chun-Ping Xiang²  Chon-Lun Pu¹  Jin Zhu²  Ming-Man Zhang¹  Zhen-Hua Guo¹  Yu-Hua Deng¹  Ying-Cun Li¹ 

[1] Department of Hepatobiliary Surgery, Children's hospital, Chongqing Medical University, Chongqing, P.R. China;Department of pathology, Children's hospital, Chongqing Medical University, Chongqing, P.R. China

关键词: Indicator;    Prognosis;    Hepatoblastoma;    Hedgehog (Hh);   

Others  :  829537
DOI  :  10.1186/2047-783X-15-11-468

 received in 2010-04-24, accepted in 2010-07-19,  发布年份 2010

【 摘 要 】

Objective

Activation of hedgehog (Hh) pathway has been implicated in the development of human malignancies. Hh as well as related downstream target genes has been extensively studied in many kinds of malignant tumours for clinical diagnostic or prognostic utilities. This study aimed at investigating whether Hh molecules provides a molecular marker of hepatoblastoma malignancy.

Methods

We obtained tissue sections from 32 patients with hepatoblastoma as well as cholestasis and normal control. Immunohistochemical analysis were performed to determine Hh signal components in human hepatoblastoma. The prognostic significance of single expression of Hh signal components were evaluated using Cox proportional hazards regression models and Kaplan-Meier survival analysis for statistical analysis.

Results

Expression of Hh signal components showed an increase in hepatoblastoma compared with chole stasis and normal tissues. There was a positive correlation between Smo or Gli1 expression and tumor clinicopathological features, such as histological type, tumor grade, tumor size and clinical stage. Both Smo or Gli1 protein high expression was significantly associated with poor prognosis by univariate analyses and multivariate analyses.

Conclusions

Abnormal Hh signaling activation plays important roles in the malignant potential of hepatoblastoma. Gli1 expression is an independent prognostic marker.

【 授权许可】

   
2010 I. Holzapfel Publishers

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Hiyama E, Yamaoka H, Matsunaga T, Hayashi Y, Ando H, Suita S, Horie H, Kaneko M, Sasaki F, Hashizume K, Nakagawara A, Ohnuma N, Yokoyama T: High expression of telomerase is an independent prognostic indicator of poor outcome in hepatoblastoma. Br J Cancer 2004, 91(5):972-979.
• [2]Wang LL, Filippi RZ, Zurakowski D, Archibald T, Vargas SO, Voss SD, Shamberger RC, Davies K, Kozakewich H, Perez-Atayde AR: Effects of neoadjuvant chemotherapy on hepatoblastoma: a morphologic and immunohistochemical study. Am J Surg Pathol 2010, 34(3):287-299.
• [3]Hou JY, Liu HC, Yeh TC, Chen SH, Wang LY, Sheu JC, Liang DC: Long-term treatment results of hepatoblastoma at a single institution in Taiwan. J Pediatr Hematol Oncol 2009, 31(10):718-722.
• [4]Sakamoto LH, DE Camargo B, Cajaiba M, Soares FA, Vettore AL: MT1G hypermethylation: a potential prognostic marker for hepatoblastoma. Pediatr Res 2010, 67(4):387-393.
• [5]Oue T, Yoneda A, Uehara S, Yamanaka H, Fukuzawa M: Increased expression of the hedgehog signaling pathway in pediatric solid malignancies. J Pediatr Surg 2010, 45(2):387-392.
• [6]von Schweinitz D, Kraus JA, Albrecht S, Koch A, Fuchs J, Pietsch T: Prognostic impact of molecular genetic alterations in hepatoblastoma. Med Pediatr Oncol 2002, 38(2):104-108.
• [7]Weber RG, Pietsch T, von Schweinitz D, Lichter P: Characterization of genomic alterations in hepatoblastomas. A role for gains on chromosomes 8q and 20 as predictors of poor outcome. Am J Pathol 2000, 157(2):571-578.
• [8]Kameda C, Tanaka H, Yamasaki A, Nakamura M, Koga K, Sato N, Kubo M, Kuroki S, Tanaka M, Katano M: The Hedgehog pathway is a possible therapeutic target for patients with estrogen receptor-negative breast cancer. Anticancer Res 2009, 29(3):871-879.
• [9]Liao X, Siu MK, Au CW, Wong ES, Chan HY, Ip PP, Ngan HY, Cheung AN: Aberrant activation of hedgehog signaling pathway in ovarian cancers: effect on prognosis, cell invasion and differentiation. Carcinogenesis 2009, 30(1):131-140.
• [10]Yoshikawa R, Nakano Y, Tao L, Koishi K, Matsumoto T, Sasako M, Tsujimura T, Hashimoto-Tamaoki T, Fujiwara Y: Hedgehog signal activation in oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy. Br J Cancer 2008, 98(10):1670-1674.
• [11]Lauth M, Toftgård R: The Hedgehog pathway as a drug target in cancer therapy. Curr Opin Investig Drugs 2007, 8(6):457-461.
• [12]Haas JE, Muczynski KA, Krailo M, Ablin A, Land V, Vietti TJ, Hammond GD: Histopathology and prognosis in childhood hepatoblastoma and hepatocarcinoma. Cancer 1989, 64(5):1082-1095.
• [13]Zhang D, Qiu L, Jin X, Guo Z, Guo C: Nuclear factorkappaB inhibition by parthenolide potentiates the efficacy of Taxol in non-small cell lung cancer in vitro and in vivo. Mol Cancer Res 2009, 7(7):1139-1149.
• [14]Yagui-Beltrán A, He B, Raz D, Kim J, Jablons DM: Novel therapies targeting signaling pathways in lung cancer. Thorac Surg Clin 2006, 16(4):379-396.
• [15]Mori Y, Okumura T, Tsunoda S, Sakai Y, Shimada Y: Gli-1 expression is associated with lymph node metastasis and tumor progression in esophageal squamous cell carcinoma. Oncology 2006, 70(5):378-389.
• [16]Chen X, Horiuchi A, Kikuchi N, Osada R, Yoshida J, Shiozawa T, Konishi I: Hedgehog signal pathway is activated in ovarian carcinomas, correlating with cell proliferation: it's inhibition leads to growth suppression and apoptosis. Cancer Sci 2007, 98(1):68-76.
• [17]Ferretti E, Di Marcotullio L, Gessi M, Mattei T, Greco A, Po A, De Smaele E, Giangaspero F, Riccardi R, Di Rocco C, Pazzaglia S, Maroder M, Alimandi M, Screpanti I, Gulino A: Alternative splicing of the ErbB-4 cytoplasmic domain and its regulation by hedgehog signaling identify distinct medulloblastoma subsets. Oncogene 2006, 25(55):7267-7273.
• [18]Nolan-Stevaux O, Lau J, Truitt ML, Chu GC, Hebrok M, Fernández-Zapico ME, Hanahan D: GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. Genes Dev 2009, 23(1):24-36.
• [19]Yoshizaki A, Nakayama T, Naito S, Wen CY, Sekine I: Expressions of sonic hedgehog, patched, smoothened and Gli-1 in human intestinal stromal tumors and their correlation with prognosis. World J Gastroenterol 2006, 12(35):5687-5691.
• [20]Kim KH, Kim JM, Choi YL, Shin YK, Lee HC, Seong IO, Kim BK, Chae SW, Chung YS, Kim SH: Expression of sonic hedgehog signaling molecules in normal, hyperplastic and carcinomatous endometrium. Pathol Int 2009, 59(5):279-287.
• [21]Hochman E, Castiel A, Jacob-Hirsch J, Amariglio N, Izraeli S: Molecular pathways regulating pro-migratory effects of Hedgehog signaling. J Biol Chem 2006, 281(45):33860-33870.
• [22]Davidson B, Goldberg I, Gotlieb WH, Kopolovic J, Risberg B, Ben-Baruch G, Reich R: Coordinated expression of integrin subunits, matrix metalloproteinases (MMP), angiogenic genes and Ets transcription factors in advanced-stage ovarian carcinoma: a possible activation pathway? Cancer Metastasis Rev 2003, 22(1):103-115.
• [23]Sodek KL, Ringuette MJ, Brown TJ: MT1-MMP is the critical determinant of matrix degradation and invasion by ovarian cancer cells. Br J Cancer 2007, 97(3):358-367.