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Erschienen in: Annals of Surgical Oncology 3/2013

01.12.2013 | Translational Research and Biomarkers

Elevated SHOX2 Expression is Associated with Tumor Recurrence of Hepatocellular Carcinoma

verfasst von: Tian Yang, MD, Han Zhang, MD, Sheng-Yun Cai, MD, Yi-Nan Shen, MD, Shou-Xin Yuan, MD, Guang-Shun Yang, MD, Meng-Chao Wu, MD, Jun-Hua Lu, MD, Feng Shen, MD, PhD

Erschienen in: Annals of Surgical Oncology | Sonderheft 3/2013

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Abstract

Background

SHOX2 (short stature homeobox 2) is a crucial transcriptional regulator in several genetic disorders and has been demonstrated to be an excellent biomarker in the diagnosis and evaluation of lung cancer. However, its expression pattern and prognostic value for hepatocellular carcinoma (HCC) are still unknown.

Methods

Expression of SHOX2 gene and protein in HCC tissues and cell lines were evaluated by RT-qPCR and western blot. Impact of RNAi-mediated SHOX2 silence on the proliferation and invasion ability of Huh7 cell line in vitro was determined by CCK-8 assay and matrigel invasion assay, respectively.

Results

Elevated expression of SHOX2 gene was significantly associated with higher incidence of tumor recurrence (n = 60, p = 0.001), absence of tumor capsule (p = 0.015), presence of tumor thrombi (p < 0.0001), and advanced TNM stage (p < 0.0001) of HCC. SHOX2 protein expression was more abundant in HCC cell lines compared with hepatic cell line (p = 0.001), which was associated with tumor recurrence (n = 40, p = 0.046). RNAi-mediated silence of SHOX2 expression significantly inhibited the proliferation (p < 0.001) and invasion (p = 0.006) of Huh7 cell line in vitro.

Conclusions

Elevated SHOX2 expression was associated with HCC recurrence, probably by enhancing proliferation and invasion capability of cancer cells.
Literatur
1.
Zurück zum Zitat Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.PubMedCrossRef Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.PubMedCrossRef
2.
Zurück zum Zitat Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.PubMedCrossRef Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.PubMedCrossRef
3.
Zurück zum Zitat Ferlay J, Shin HR, Bray F, Forman D, Mathers CD, Parkin DM. GLOBOCAN 2008, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10. Lyon, France: International Agency for Research on Cancer; 2010. http://globocan.iarc.fr. 2010. Accessed 17 Aug 2010. Ferlay J, Shin HR, Bray F, Forman D, Mathers CD, Parkin DM. GLOBOCAN 2008, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10. Lyon, France: International Agency for Research on Cancer; 2010. http://​globocan.​iarc.​fr. 2010. Accessed 17 Aug 2010.
4.
Zurück zum Zitat Poon D, Anderson BO, Chen LT, Tanaka K, Lau WY, Van Cutsem E, et al. Management of hepatocellular carcinoma in Asia: consensus statement from the Asian Oncology Summit 2009. Lancet Oncol. 2009;10:1111–8.PubMedCrossRef Poon D, Anderson BO, Chen LT, Tanaka K, Lau WY, Van Cutsem E, et al. Management of hepatocellular carcinoma in Asia: consensus statement from the Asian Oncology Summit 2009. Lancet Oncol. 2009;10:1111–8.PubMedCrossRef
5.
Zurück zum Zitat Liu H, Espinoza-Lewis RA, Chen C, Hu X, Zhang Y, Chen Y. The role of Shox2 in SAN development and function. Pediatr Cardiol. 2012;33:882–9.PubMedCrossRef Liu H, Espinoza-Lewis RA, Chen C, Hu X, Zhang Y, Chen Y. The role of Shox2 in SAN development and function. Pediatr Cardiol. 2012;33:882–9.PubMedCrossRef
6.
Zurück zum Zitat Blaschke RJ, Monaghan AP, Schiller S, Schechinger B, Rao E, Padilla-Nash H, et al. SHOT, a SHOX-related homeobox gene, is implicated in craniofacial, brain, heart, and limb development. Proc Natl Acad Sci U S A. 1998;95:2406–11.PubMedCrossRef Blaschke RJ, Monaghan AP, Schiller S, Schechinger B, Rao E, Padilla-Nash H, et al. SHOT, a SHOX-related homeobox gene, is implicated in craniofacial, brain, heart, and limb development. Proc Natl Acad Sci U S A. 1998;95:2406–11.PubMedCrossRef
7.
Zurück zum Zitat Blaschke RJ, Hahurij ND, Kuijper S, Just S, Wisse LJ, Deissler K, et al. Targeted mutation reveals essential functions of the homeodomain transcription factor Shox2 in sinoatrial and pacemaking development. Circulation. 2007;115:1830–8.PubMedCrossRef Blaschke RJ, Hahurij ND, Kuijper S, Just S, Wisse LJ, Deissler K, et al. Targeted mutation reveals essential functions of the homeodomain transcription factor Shox2 in sinoatrial and pacemaking development. Circulation. 2007;115:1830–8.PubMedCrossRef
8.
Zurück zum Zitat Clement-Jones M, Schiller S, Rao E, Blaschke RJ, Zuniga A, Zeller R, et al. The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome. Hum Mol Genet. 2000;9:695–702.PubMedCrossRef Clement-Jones M, Schiller S, Rao E, Blaschke RJ, Zuniga A, Zeller R, et al. The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome. Hum Mol Genet. 2000;9:695–702.PubMedCrossRef
9.
Zurück zum Zitat Liu H, Chen CH, Espinoza-Lewis RA, Jiao Z, Sheu I, Hu X, et al. Functional redundancy between human SHOX and mouse Shox2 genes in the regulation of sinoatrial node formation and pacemaking function. J Biol Chem. 2011;286:17029–38.PubMedCrossRef Liu H, Chen CH, Espinoza-Lewis RA, Jiao Z, Sheu I, Hu X, et al. Functional redundancy between human SHOX and mouse Shox2 genes in the regulation of sinoatrial node formation and pacemaking function. J Biol Chem. 2011;286:17029–38.PubMedCrossRef
10.
Zurück zum Zitat Dietrich D, Hasinger O, Liebenberg V, Field JK, Kristiansen G, Soltermann A. DNA methylation of the homeobox genes PITX2 and SHOX2 predicts outcome in non-small-cell lung cancer patients. Diagn Mol Pathol. 2012;21:93–104.PubMedCrossRef Dietrich D, Hasinger O, Liebenberg V, Field JK, Kristiansen G, Soltermann A. DNA methylation of the homeobox genes PITX2 and SHOX2 predicts outcome in non-small-cell lung cancer patients. Diagn Mol Pathol. 2012;21:93–104.PubMedCrossRef
11.
Zurück zum Zitat Kneip C, Schmidt B, Seegebarth A, Weickmann S, Fleischhacker M, Liebenberg V, et al. SHOX2 DNA methylation is a biomarker for the diagnosis of lung cancer in plasma. J Thorac Oncol. 2011;6:1632–8.PubMedCrossRef Kneip C, Schmidt B, Seegebarth A, Weickmann S, Fleischhacker M, Liebenberg V, et al. SHOX2 DNA methylation is a biomarker for the diagnosis of lung cancer in plasma. J Thorac Oncol. 2011;6:1632–8.PubMedCrossRef
12.
Zurück zum Zitat Schneider KU, Dietrich D, Fleischhacker M, Leschber G, Merk J, Schäper F, et al. Correlation of SHOX2 gene amplification and DNA methylation in lung cancer tumors. BMC Cancer. 2011;11:102.PubMedCrossRef Schneider KU, Dietrich D, Fleischhacker M, Leschber G, Merk J, Schäper F, et al. Correlation of SHOX2 gene amplification and DNA methylation in lung cancer tumors. BMC Cancer. 2011;11:102.PubMedCrossRef
13.
Zurück zum Zitat Dietrich D, Kneip C, Raji O, Liloglou T, Seegebarth A, Schlegel T, et al. Performance evaluation of the DNA methylation biomarker SHOX2 for the aid in diagnosis of lung cancer based on the analysis of bronchial aspirates. Int J Oncol. 2012;40:825–32.PubMed Dietrich D, Kneip C, Raji O, Liloglou T, Seegebarth A, Schlegel T, et al. Performance evaluation of the DNA methylation biomarker SHOX2 for the aid in diagnosis of lung cancer based on the analysis of bronchial aspirates. Int J Oncol. 2012;40:825–32.PubMed
14.
Zurück zum Zitat Schmidt B, Liebenberg V, Dietrich D, Schlegel T, Kneip C, Seegebarth A, et al. SHOX2 DNA methylation is a biomarker for the diagnosis of lung cancer based on bronchial aspirates. BMC Cancer. 2010;10:600.PubMedCrossRef Schmidt B, Liebenberg V, Dietrich D, Schlegel T, Kneip C, Seegebarth A, et al. SHOX2 DNA methylation is a biomarker for the diagnosis of lung cancer based on bronchial aspirates. BMC Cancer. 2010;10:600.PubMedCrossRef
15.
Zurück zum Zitat Yang T, Cai SY, Zhang J, Lu JH, Lin C, Zhai J, et al. Kruppel-like factor 8 is a new Wnt/beta-catenin signaling target gene and regulator in hepatocellular carcinoma. PLoS One. 2012;7:e39668.PubMedCrossRef Yang T, Cai SY, Zhang J, Lu JH, Lin C, Zhai J, et al. Kruppel-like factor 8 is a new Wnt/beta-catenin signaling target gene and regulator in hepatocellular carcinoma. PLoS One. 2012;7:e39668.PubMedCrossRef
16.
Zurück zum Zitat Yang T, Lu JH, Lin C, Shi S, Chen TH, Zhao RH, et al. Concomitant lung metastasis in patients with advanced hepatocellular carcinoma. World J Gastroenterol. 2012;18:2533–9.PubMedCrossRef Yang T, Lu JH, Lin C, Shi S, Chen TH, Zhao RH, et al. Concomitant lung metastasis in patients with advanced hepatocellular carcinoma. World J Gastroenterol. 2012;18:2533–9.PubMedCrossRef
17.
Zurück zum Zitat Ke AW, Shi GM, Zhou J, Wu FZ, Ding ZB, Hu MY, et al. Role of overexpression of CD151 and/or c-Met in predicting prognosis of hepatocellular carcinoma. Hepatology. 2009;49:491–503.PubMedCrossRef Ke AW, Shi GM, Zhou J, Wu FZ, Ding ZB, Hu MY, et al. Role of overexpression of CD151 and/or c-Met in predicting prognosis of hepatocellular carcinoma. Hepatology. 2009;49:491–503.PubMedCrossRef
18.
Zurück zum Zitat 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;25:402–8.PubMedCrossRef 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;25:402–8.PubMedCrossRef
19.
Zurück zum Zitat Ke AW, Shi GM, Zhou J, Huang XY, Shi YH, Ding ZB, et al. CD151 amplifies signaling by integrin alpha6beta1 to PI3K and induces the epithelial-mesenchymal transition in HCC cells. Gastroenterology. 2011;140:1629–41.PubMedCrossRef Ke AW, Shi GM, Zhou J, Huang XY, Shi YH, Ding ZB, et al. CD151 amplifies signaling by integrin alpha6beta1 to PI3K and induces the epithelial-mesenchymal transition in HCC cells. Gastroenterology. 2011;140:1629–41.PubMedCrossRef
20.
Zurück zum Zitat Shi GM, Xu Y, Fan J, Zhou J, Yang XR, Qiu SJ, et al. Identification of side population cells in human hepatocellular carcinoma cell lines with stepwise metastatic potentials. J Cancer Res Clin Oncol. 2008;134:1155–63.PubMedCrossRef Shi GM, Xu Y, Fan J, Zhou J, Yang XR, Qiu SJ, et al. Identification of side population cells in human hepatocellular carcinoma cell lines with stepwise metastatic potentials. J Cancer Res Clin Oncol. 2008;134:1155–63.PubMedCrossRef
21.
Zurück zum Zitat Forner A, Hessheimer AJ, Isabel Real M, Bruix J. Treatment of hepatocellular carcinoma. Crit Rev Oncol Hematol. 2006;60:89–98.PubMedCrossRef Forner A, Hessheimer AJ, Isabel Real M, Bruix J. Treatment of hepatocellular carcinoma. Crit Rev Oncol Hematol. 2006;60:89–98.PubMedCrossRef
22.
Zurück zum Zitat Mathurin P, Raynard B, Dharancy S, Kirzin S, Fallik D, Pruvot FR, et al. Meta-analysis: evaluation of adjuvant therapy after curative liver resection for hepatocellular carcinoma. Aliment Pharmacol Ther. 2003;17:1247–61.PubMedCrossRef Mathurin P, Raynard B, Dharancy S, Kirzin S, Fallik D, Pruvot FR, et al. Meta-analysis: evaluation of adjuvant therapy after curative liver resection for hepatocellular carcinoma. Aliment Pharmacol Ther. 2003;17:1247–61.PubMedCrossRef
23.
Zurück zum Zitat Zhou XD, Tang ZY, Yang BH, Lin ZY, Ma ZC, Ye SL, et al. Experience of 1000 patients who underwent hepatectomy for small hepatocellular carcinoma. Cancer. 2001;91:1479–86.PubMedCrossRef Zhou XD, Tang ZY, Yang BH, Lin ZY, Ma ZC, Ye SL, et al. Experience of 1000 patients who underwent hepatectomy for small hepatocellular carcinoma. Cancer. 2001;91:1479–86.PubMedCrossRef
Metadaten
Titel
Elevated SHOX2 Expression is Associated with Tumor Recurrence of Hepatocellular Carcinoma
verfasst von
Tian Yang, MD
Han Zhang, MD
Sheng-Yun Cai, MD
Yi-Nan Shen, MD
Shou-Xin Yuan, MD
Guang-Shun Yang, MD
Meng-Chao Wu, MD
Jun-Hua Lu, MD
Feng Shen, MD, PhD
Publikationsdatum
01.12.2013
Verlag
Springer US
Erschienen in
Annals of Surgical Oncology / Ausgabe Sonderheft 3/2013
Print ISSN: 1068-9265
Elektronische ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-013-3132-1

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