The oncoprotein and stem cell renewal factor BMI1 associates with poor clinical outcome in oesophageal cancer patients undergoing preoperative chemoradiotherapy

BMC Cancer

Reigetsu Yoshikawa¹  Tohru Tsujimura⁴  Lihua Tao⁴  Norihiko Kamikonya²  Yoshinori Fujiwara³ 

[1] Department of Surgery, Kanzaki Hospital, 3-1-10, Hama, Amagasaki, Hyogo, 661-0967, Japan

[2] Department of Radiology, Hyogo College of Medicine, 1–1, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan

[3] Department of Digestive Surgery, Nara Hospital, Kinki University school of Medicine, 1248-1, Otoda-cho, Ikoma, Nara, 630-0293, Japan

[4] Department of Pathology, Hyogo College of Medicine, 1–1, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan

关键词: p16^INK4A;    Oesophageal cancer;    Hedgehog (Hh);    BMI1;    Chemoradiotherapy (CRT);    Cancer stem cell;   

Others  :  1080148
DOI  :  10.1186/1471-2407-12-461

 received in 2012-02-28, accepted in 2012-10-01,  发布年份 2012

【 摘 要 】

Background

The polycomb group (PcG) family BMI1, acting downstream of the hedgehog (Hh) pathway, plays an essential role in the self-renewal of haematopoietic, neural, and intestinal stem cells, and is dysregulated in many types of cancer. Our recent report has demonstrated that Hh signalling activation can predict very earlier relapse of oesophageal cancers. As data were not available on the clinical role of BMI1 expression in oesophageal cancers after chemoradiotherapy (CRT), we analysed whether it could be also used to predict disease progression and prognosis in oesophageal cancer patients undergoing trimodality therapy of preoperative CRT and oesophagectomy.

Methods

Expressions of BMI1 and p16^INK4A, a downstream target of PcG, were analysed in 78 patients with histologically confirmed oesophageal squamous cell carcinoma (ESCC) after preoperative CRT by immunohistochemical staining. The association of BMI1 and p16^INK4A expression with clinicopathologic characteristics was analysed by χ²-test. Survival analysis was carried out by the log-rank test using Kaplan-Meier method.

Results

Among 78 ESCC patients, 24 patients (30.8%) showed BMI1 positivity, mainly localised in the nuclei of tumour cells. Patients harbouring BMI1-positive tumour cells showed significantly poorer prognoses than those without such cells or residual tumours (mean disease-free survival (DFS) time 16.8 vs 71.2 months; 3-yr DFS 13.3% vs 49.9%, P=0.002; mean OS time 21.8 vs 76.6 months; 3-yr OS 16.2% vs 54.9%, P=0.0005). There was no significant correlation between p16^INK4A expression and BMI1 expression.

Conclusions

Our study shows that BMI1 expression is a predictor of early relapse and poor prognosis in ESCC after CRT. These findings suggest that BMI1 signal activation might be involved in promoting cancer regrowth and progression after CRT, and might be indicative of emergence of ‘more aggressive’ cancer progenitor cells.

【 授权许可】

   
2012 Yoshikawa et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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【 参考文献 】

• [1]Parkin DM, Bray F, Ferlay J, Pisani P: Global cancer statistics, 2002. CA Cancer J Clin 2005, 55:74-108.
• [2]Ando N, Ozawa S, Kitagawa Y, Shinozawa Y, Kitajima M: Improvement in the result of surgical treatment of advanced squamous esophageal carcinoma during 15 consecutive years. Ann Surg 2000, 232:225-232.
• [3]Igaki H, Kato H, Ando N, Shinoda M, Shimizu H, Nakamura T, Ozawa S, Yabusaki H, Aoyama N, Kurita A, Fukuda H: A randomized trial of postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus neoadjuvant chemotherapy for clinical stage II/III squamous cell carcinoma of the thoracic esophagus (JCOG 9907). J Clin Oncol 2008, 26:4510.
• [4]Chirieac L, Swisher SG, Ajani JA, Komaki RR, Correa AM, Morris JS, Roth JA, Rashid A, Hamilton SR, Wu TT: Posttherapy pathologic stage predicts survival in patients with esophageal carcinoma receiving preoperative chemoradiation. Cancer 2005, 103:1347-1355.
• [5]Fujiwara Y, Kamikonya N, Inoue T, Koishi K, Yoshikawa R, Nakao K, Yagyu R, Nishiwaki M, Fujiwara M, Kojima S, Nakagawa K, Yamamura T: Chemoradiotherapy for T3 and T4 squamous cell carcinoma of the esophagus using low-dose FP and radiation: A preliminary report. Oncol Rep 2005, 14:1177-1182.
• [6]Coia LR, Minsky BD, Berkey BA, John MJ, Haller D, Landry J, Pisansky TM, Willett CG, Hoffman JP, Owen JB, Hanks GE: Outcome of patients receiving radiation for cancer of the esophagus: results of the 1992–1994 Patterns of Care Study. J Clin Oncol 2000, 18:455-462.
• [7]Iyer R, Wilkinson N, Demmy T, Javle M: Controversies in the multimodality management of locally advanced esophageal cancer: evidence-based review of surgery alone and combined-modality therapy. Ann Surg Oncol 2004, 11:665-673.
• [8]Reya T, Morrison SJ, Clarke MF, Weissman IL: Stem cells, cancer, and cancer stem cells. Nature 2001, 414:105-111.
• [9]Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF: Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003, 100:3983-3988.
• [10]Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S, Crowley D, Bronson RT, Jacks T: Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 2005, 121:823-835.
• [11]O'Brien CA, Pollett A, Gallinger S, Dick JE: A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007, 445:106-110.
• [12]Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De MR: Identification and expansion of human colon-cancer-initiating cells. Nature 2007, 445:111-115.
• [13]Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM: Identification of pancreatic cancer stem cells. Cancer Res 2007, 67:1030-1037.
• [14]van Lohuizen M, Verbeek S, Scheijen B, Wientjens E, van der Gulden H, Berns A: Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell 1991, 65:737-752.
• [15]Haupt Y, Alexander WS, Barri G, Klinken SP, Adams JM: Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice. Cell 1991, 65:753-763.
• [16]Pirrotta V: Polycombing the genome: PcG, trxG, and chromatin silencing. Cell 1998, 93:333-336.
• [17]Jacobs JJ, Scheijen B, Voncken JW, Kieboom K, Berns A, van Lohuizen M: Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev 1999, 13:2678-2690.
• [18]Jacobs JJ, Kieboom K, Marino S, DePinho RA, van Lohuizen M: The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 1999, 397:164-168.
• [19]Smith KS, Chanda SK, Lingbeek M, Ross DT, Botstein D, van Lohuizen M, Cleary ML: Bmi-1 regulation of INK4A-ARF is a downstream requirement for transformation of hematopoietic progenitors by E2a-Pbx1. Mol Cell 2003, 12:393-400.
• [20]Spivakov M, Fisher AG: Epigenetic signatures of stem-cell identity. Nat Rev Genet 2007, 8:263-271.
• [21]Vonlanthen S, Heighway J, Altermatt HJ, Gugger M, Kappeler A, Borner MM, van Lohuizen M, Betticher DC: The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression. Br J Cancer 2001, 84:1372-1376.
• [22]Leung C, Lingbeek M, Shakhova O, Liu J, Tanger E, Saremaslani P, Van Lohuizen M, Marino S: Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature 2004, 428:337-341.
• [23]Glinsky GV, Berezovska O, Glinskii AB: Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer. J Clin Invest 2005, 115:1503-1521.
• [24]Kim JH, Yoon SY, Kim CN, Joo JH, Moon SK, Choe IS, Choe YK, Kim JW: The Bmi-1 oncoprotein is overexpressed in human colorectal cancer and correlates with the reduced p16INK4a/p14ARF proteins. Cancer Lett 2004, 203:217-224.
• [25]Dimri GP, Martinez JL, Jacobs JJ, Keblusek P, Itahana K, Van Lohuizen M, Campisi J, Wazer DE, Band V: The Bmi-1 oncogene induces telomerase activity and immortalizes human mammary epithelial cells. Cancer Res 2002, 62:4736-4745.
• [26]Liu WL, Guo XZ, Zhang LJ, Wang JY, Zhang G, Guan S, Chen YM, Kong QL, Xu LH, Li MZ, Song LB, Zeng MS: Prognostic relevance of Bmi-1 expression and autoantibodies in esophageal squamous cell carcinoma. BMC Cancer 2010, 10:467. BioMed Central Full Text
• [27]Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, Suri P, Wicha MS: Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 2006, 66:6063-6071.
• [28]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, 98:1670-1674.
• [29]Yoshikawa R, Fujiwara Y, Koishi K, Kojima S, Matsumoto T, Yanagi H, Yamamura T, Hashimoto-Tamaoki T, Nishigami T, Tsujimura T: Cyclooxygenase-2 expression after preoperative chemoradiotherapy correlates with more frequent esophageal cancer recurrence. World J Gastroenterol 2007, 13:2283-2288.
• [30]Koishi K, Yoshikawa R, Tsujimura T, Hashimoto-Tamaoki T, Kojima S, Yanagi H, Yamamura T, Fujiwara Y: Persistent CXCR4 expression after preoperative chemoradiotherapy predicts early recurrence and poor prognosis in esophageal cancer. World J Gastroenterol 2006, 12:7585-7590.
• [31]Glinsky GV: "Stemness" genomics law governs clinical behavior of human cancer: implications for decision making in disease management. J Clin Oncol 2008, 26:2846-2853.
• [32]Siddique HR, Saleem M: Role of BMI1, a Stem Cell Factor, in Cancer Recurrence and Chemoresistance: Preclinical and Clinical Evidences. Stem Cells 2012, 30:372-378.
• [33]Sims-Mourtada J, Izzo JG, Ajani J, Chao KS: Sonic Hedgehog promotes multiple drug resistance by regulation of drug transport. Oncogene 2007, 26:5674-5679.
• [34]Berezovska OP, Glinskii AB, Yang Z, Li XM, Hoffman RM, Glinsky GV: Essential role for activation of the Polycomb group (PcG) protein chromatin silencing pathway in metastatic prostate cancer. Cell Cycle 2006, 5:1886-1901.
• [35]Mihic-Probst D, Kuster A, Kilgus S, Bode-Lesniewska B, Ingold-Heppner B, Leung C, Storz M, Seifert B, Marino S, Schraml P, Dummer R, Moch H: Consistent expression of the stem cell renewal factor BMI-1 in primary and metastatic melanoma. Int J Cancer 2007, 121:1764-1770.
• [36]Takeuchi H, Ozawa S, Shih CH, Ando N, Kitagawa Y, Ueda M, Kitajima M: Loss of p16INK4a expression is associated with vascular endothelial growth factor expression in squamous cell carcinoma of the esophagus. Int J Cancer 2004, 109:483-490.