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Erschienen in: Journal of Cancer Research and Clinical Oncology 10/2012

01.10.2012 | Original Paper

Nanog siRNA plus Cisplatin may enhance the sensitivity of chemotherapy in esophageal cancer

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 10/2012

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Abstract

Background

Cancer stem cells are regarded as the origin of tumors that can proliferate, relapse, and metastasize. Nanog, with its capacity to maintain the pluripotency and regulate proliferation and prevent differentiation, is one of the most important core markers of cancer stem cells. Studying the role of Nanog in esophageal squamous cell carcinoma (ESCC), therefore, has important implications.

Methods

In the present study, we first detected the expression of Nanog in the ESCC and cell lines by RT-PCR, immunofluorescence, and immunohistochemisty. Then, we used small interfering RNA (siRNA) to block Nanog expression while evaluating the effect of Nanog siRNA on cell apoptosis and the combined effects with Cisplatin in ESCC cell lines.

Results

The results showed that both mRNA and protein-level Nanog are overexpressed in ESCC tissues compared with their normal counterparts, and the increased occurrence of Nanog expression was positively correlated with TNM stages and histopathological differentiation of ESCC patients (p < 0.01). At the same time, Nanog siRNA efficiently decreased Nanog expression and induced cell apoptosis. Treatment with Nanog siRNA in combination with Cisplatin, therefore, enhanced chemosensitivity.

Conclusion

The present study’s results suggest that detecting Nanog might be helpful for diagnosing ESCC, and Nanog siRNA combined with Cisplatin may be a feasible strategy to enhance the sensitivity of chemotherapy in patients with ESCC.
Literatur
Zurück zum Zitat Ben-Porath I, Thomson MW, Carey VJ et al (2008) An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 40:499–507PubMedCrossRef Ben-Porath I, Thomson MW, Carey VJ et al (2008) An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 40:499–507PubMedCrossRef
Zurück zum Zitat Bojko P, Scharifi M, Stössel K et al (2002) Comparison of processing four and five times the patients’ blood volume during peripheral blood stem cell collection and analysis of CD34+38– and CD34+49d+ subsets during apheresis. J Cancer Res Clin Oncol 128(1):19–28PubMedCrossRef Bojko P, Scharifi M, Stössel K et al (2002) Comparison of processing four and five times the patients’ blood volume during peripheral blood stem cell collection and analysis of CD34+38– and CD34+49d+ subsets during apheresis. J Cancer Res Clin Oncol 128(1):19–28PubMedCrossRef
Zurück zum Zitat Bourguignon LY, Peyrollier K, Xia W, Gilad E (2008) Hyaluronan-CD44 interaction activates stem cell marker Nanog, Stat-3-mediated MDR1 gene expression, and ankyrin-regulated multidrug efflux in breast and ovarian tumor cells. J Biol Chem 283:17635–17651PubMedCrossRef Bourguignon LY, Peyrollier K, Xia W, Gilad E (2008) Hyaluronan-CD44 interaction activates stem cell marker Nanog, Stat-3-mediated MDR1 gene expression, and ankyrin-regulated multidrug efflux in breast and ovarian tumor cells. J Biol Chem 283:17635–17651PubMedCrossRef
Zurück zum Zitat Chang DF, Tsai SC, Wang XC et al (2009) Molecular characterization of the human Nanog protein. Stem Cells 27:812–821PubMedCrossRef Chang DF, Tsai SC, Wang XC et al (2009) Molecular characterization of the human Nanog protein. Stem Cells 27:812–821PubMedCrossRef
Zurück zum Zitat Chen R, Xiao W, Li D et al (2011) Combination of simvastatin and imatinib sensitizes the CD34+ cells in K562 to cell death. Med Oncol 28:528–531PubMed Chen R, Xiao W, Li D et al (2011) Combination of simvastatin and imatinib sensitizes the CD34+ cells in K562 to cell death. Med Oncol 28:528–531PubMed
Zurück zum Zitat Chiou SH, Yu CC, Huang CY (2008) Positive correlations of Oct-4 and Nanog in oral cancer stem-like cells and high-grade oral squamous cell carcinoma. Clin Cancer Res 14:4085–4095PubMedCrossRef Chiou SH, Yu CC, Huang CY (2008) Positive correlations of Oct-4 and Nanog in oral cancer stem-like cells and high-grade oral squamous cell carcinoma. Clin Cancer Res 14:4085–4095PubMedCrossRef
Zurück zum Zitat Clarke MF, Dick JE, Dirks PB et al (2006) Cancer stem cells N perspectives on current status and future directions: AACR workshop on cancer stem cells. Cancer Res 66:9339–9344PubMedCrossRef Clarke MF, Dick JE, Dirks PB et al (2006) Cancer stem cells N perspectives on current status and future directions: AACR workshop on cancer stem cells. Cancer Res 66:9339–9344PubMedCrossRef
Zurück zum Zitat Darr H, Mayshar Y, Benvenisty N (2006) Overexpression of NANOG in human ES cells enables feeder-free growth while inducing primitive ectoderm features. Development 133:1193–1201PubMedCrossRef Darr H, Mayshar Y, Benvenisty N (2006) Overexpression of NANOG in human ES cells enables feeder-free growth while inducing primitive ectoderm features. Development 133:1193–1201PubMedCrossRef
Zurück zum Zitat Dennis N (2002) Common control for cancer, stem cells. Science 298:1869–1875CrossRef Dennis N (2002) Common control for cancer, stem cells. Science 298:1869–1875CrossRef
Zurück zum Zitat Ezeh UI, Turek PJ, Reijo RA et al (2005) Human embryonic stem cell genes OCT4, NANOG, STELLAR, and GDF3 are expressed in both seminoma and breast carcinoma. Am Cancer Soc 104:2255–2266 Ezeh UI, Turek PJ, Reijo RA et al (2005) Human embryonic stem cell genes OCT4, NANOG, STELLAR, and GDF3 are expressed in both seminoma and breast carcinoma. Am Cancer Soc 104:2255–2266
Zurück zum Zitat Freberg CT, Dahl JA, Timoskainen S et al (2007) Epigenetic reprogramming of OCT4 and NANOG regulatory regions by embryonal carcinoma cell extract. Mol Biol Cell 18:1543–1553PubMedCrossRef Freberg CT, Dahl JA, Timoskainen S et al (2007) Epigenetic reprogramming of OCT4 and NANOG regulatory regions by embryonal carcinoma cell extract. Mol Biol Cell 18:1543–1553PubMedCrossRef
Zurück zum Zitat Fujii H, Honoki K, Tsujiuchi T et al (2009) Sphem forming stem-like cell populations with drug resistance in human sarcoma cell lines. Int J Oncol 34:1381–1386 Fujii H, Honoki K, Tsujiuchi T et al (2009) Sphem forming stem-like cell populations with drug resistance in human sarcoma cell lines. Int J Oncol 34:1381–1386
Zurück zum Zitat Gu G, Yuan J, Wills M et al (2007) Prostate cancer cells with stem cell characteristics reconstitute the original human tumor in vivo. Cancer Res 67:4807–4815PubMedCrossRef Gu G, Yuan J, Wills M et al (2007) Prostate cancer cells with stem cell characteristics reconstitute the original human tumor in vivo. Cancer Res 67:4807–4815PubMedCrossRef
Zurück zum Zitat Hart AH, Hartley L, Ibrahim M et al (2004) Identification, cloning and expression analysis of the pluripotency promoting Nanog genes in mouse and human. Dev Dyn 230:187–198PubMedCrossRef Hart AH, Hartley L, Ibrahim M et al (2004) Identification, cloning and expression analysis of the pluripotency promoting Nanog genes in mouse and human. Dev Dyn 230:187–198PubMedCrossRef
Zurück zum Zitat Hoei-Hansen CE, Kraggerud SM, Abeler VM (2007) Ovarian dysgerminomas are characterised by frequent KIT mutations and abundant expression of pluripotency markers. Mol Cancer 2:6–12 Hoei-Hansen CE, Kraggerud SM, Abeler VM (2007) Ovarian dysgerminomas are characterised by frequent KIT mutations and abundant expression of pluripotency markers. Mol Cancer 2:6–12
Zurück zum Zitat Huang D, Gao Q, Guo L et al (2009) Isolation and identification of cancer stem-like cells in esophageal carcinoma cell lines. Stem Cells 18:465–473CrossRef Huang D, Gao Q, Guo L et al (2009) Isolation and identification of cancer stem-like cells in esophageal carcinoma cell lines. Stem Cells 18:465–473CrossRef
Zurück zum Zitat Lee TK, Castilho A, Cheung VC, et al (2011) CD24+ liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation.Cell Stem Cell 9(1):50–63 Lee TK, Castilho A, Cheung VC, et al (2011) CD24+ liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation.Cell Stem Cell 9(1):50–63
Zurück zum Zitat Lin T, Ding YQ, Li JM (2011) Overexpression of Nanog protein is associated with poor prognosis in gastric adenocarcinoma. Med Oncol. [Epub ahead of print] Lin T, Ding YQ, Li JM (2011) Overexpression of Nanog protein is associated with poor prognosis in gastric adenocarcinoma. Med Oncol. [Epub ahead of print]
Zurück zum Zitat Liu SJ, Cai ZW, Liu YJ et al (2004) Role of nucleostemin in growth regulation of gastric cancer, liver cancer and other malignancies. World J Gastroenterol 10:1246–1249PubMed Liu SJ, Cai ZW, Liu YJ et al (2004) Role of nucleostemin in growth regulation of gastric cancer, liver cancer and other malignancies. World J Gastroenterol 10:1246–1249PubMed
Zurück zum Zitat Mitsui K, Tokuzawa Y, Itoh H, Segawa K et al (2003) The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113:631–642PubMedCrossRef Mitsui K, Tokuzawa Y, Itoh H, Segawa K et al (2003) The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113:631–642PubMedCrossRef
Zurück zum Zitat Pan G, Thomson JA (2007) Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Res 17:42–49PubMedCrossRef Pan G, Thomson JA (2007) Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Res 17:42–49PubMedCrossRef
Zurück zum Zitat Ratajczak MZ, Machalinski B, Wojakowski W et al (2007) A hypothesis for an embryonic origin of pluripotent Oct-4(+) stem cells in adult bone marrow and other tissues. Leukemia 21:860–867PubMed Ratajczak MZ, Machalinski B, Wojakowski W et al (2007) A hypothesis for an embryonic origin of pluripotent Oct-4(+) stem cells in adult bone marrow and other tissues. Leukemia 21:860–867PubMed
Zurück zum Zitat Santagata S, Ligon KL, Hornick JL (2007) Embryonic stem cell transcription factor signatures in the diagnosis of primary and metastatic germ cell tumors. Am J Surg Pathol 31:836–845PubMedCrossRef Santagata S, Ligon KL, Hornick JL (2007) Embryonic stem cell transcription factor signatures in the diagnosis of primary and metastatic germ cell tumors. Am J Surg Pathol 31:836–845PubMedCrossRef
Zurück zum Zitat Seigel GM, Hackam AS, Ganguly A et al (2007) Human embryonic and neuronal stem cell markers in retinoblastoma. Mol Vis 13:823–832PubMed Seigel GM, Hackam AS, Ganguly A et al (2007) Human embryonic and neuronal stem cell markers in retinoblastoma. Mol Vis 13:823–832PubMed
Zurück zum Zitat Singh SK, Clarke ID, Terasaki M et al (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828PubMed Singh SK, Clarke ID, Terasaki M et al (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828PubMed
Zurück zum Zitat Siu MK, Wong ES, Chan HY et al (2008) Overexpression of NANOG in gestational trophoblastic diseases. Am J Pathol 173:1165–1172PubMedCrossRef Siu MK, Wong ES, Chan HY et al (2008) Overexpression of NANOG in gestational trophoblastic diseases. Am J Pathol 173:1165–1172PubMedCrossRef
Zurück zum Zitat Stoner GD, Gupta A (2001) Etiology and chemoprevention of esophageal squamous cell carcinoma. Carcinogenesis 22:1737–1746PubMedCrossRef Stoner GD, Gupta A (2001) Etiology and chemoprevention of esophageal squamous cell carcinoma. Carcinogenesis 22:1737–1746PubMedCrossRef
Zurück zum Zitat Tiezzi DG, Valejo FA, Marana HR, et al (2011) CD44(+)/CD24 (−) cells and lymph node metastasis in stage I and II invasive ductal carcinoma of the breast. Med Oncol. [Epub ahead of print] Tiezzi DG, Valejo FA, Marana HR, et al (2011) CD44(+)/CD24 (−) cells and lymph node metastasis in stage I and II invasive ductal carcinoma of the breast. Med Oncol. [Epub ahead of print]
Zurück zum Zitat Trosko JE (2006) From adult stem cells to cancer stem cells: Oct-4 gene, cell–cell communication, and hormones during tumor promotion. Ann N Y Acad Sci 1089:36–58PubMedCrossRef Trosko JE (2006) From adult stem cells to cancer stem cells: Oct-4 gene, cell–cell communication, and hormones during tumor promotion. Ann N Y Acad Sci 1089:36–58PubMedCrossRef
Zurück zum Zitat Wang SH, Tsai MS, Chiang MF et al (2003) A novel NK-type homeobox gene, ENK (early embryo specific NK), preferentially expressed in embryonic stem cells. Gene Expr Patterns 3:99–103PubMedCrossRef Wang SH, Tsai MS, Chiang MF et al (2003) A novel NK-type homeobox gene, ENK (early embryo specific NK), preferentially expressed in embryonic stem cells. Gene Expr Patterns 3:99–103PubMedCrossRef
Zurück zum Zitat Wang Q, He W, Lu C, Wang Z et al (2009) Oct3/4 and Sox2 are significantly associated with an unfavorable clinical outcome in human esophageal squamous cell carcinoma. Anticancer Res 29:1233–1241PubMed Wang Q, He W, Lu C, Wang Z et al (2009) Oct3/4 and Sox2 are significantly associated with an unfavorable clinical outcome in human esophageal squamous cell carcinoma. Anticancer Res 29:1233–1241PubMed
Zurück zum Zitat Yasuda SY, Tsuneyoshi N, Sumi T et al (2006) NANOG maintains self-renewal of primate ES cells in the absence of a feeder layer. Genes Cells 11:1115–1123PubMedCrossRef Yasuda SY, Tsuneyoshi N, Sumi T et al (2006) NANOG maintains self-renewal of primate ES cells in the absence of a feeder layer. Genes Cells 11:1115–1123PubMedCrossRef
Zurück zum Zitat Ye F, Zhou C, Cheng Q et al (2008) Stem-cell-abundant proteins Nanog, Nucleostemin and Musashi1 are highly expressed in malignant cervical epithelial cells. BMC Cancer 8:108–113PubMedCrossRef Ye F, Zhou C, Cheng Q et al (2008) Stem-cell-abundant proteins Nanog, Nucleostemin and Musashi1 are highly expressed in malignant cervical epithelial cells. BMC Cancer 8:108–113PubMedCrossRef
Zurück zum Zitat Zhang S, Ding F, Luo A et al (2007) XIAP is highly expressed in esophageal cancer and its downregulation by RNAi sensitizes esophageal carcinoma cell lines to chemotherapeutics. Cancer Biol Ther 6:973–980PubMed Zhang S, Ding F, Luo A et al (2007) XIAP is highly expressed in esophageal cancer and its downregulation by RNAi sensitizes esophageal carcinoma cell lines to chemotherapeutics. Cancer Biol Ther 6:973–980PubMed
Zurück zum Zitat Zou X, Lu F, Zhang S (2002) Characteristics of esophageal cancer mortality in China in 1990–1992. Bull Chin Cancer 11:446–449 Zou X, Lu F, Zhang S (2002) Characteristics of esophageal cancer mortality in China in 1990–1992. Bull Chin Cancer 11:446–449
Metadaten
Titel
Nanog siRNA plus Cisplatin may enhance the sensitivity of chemotherapy in esophageal cancer
Publikationsdatum
01.10.2012
Erschienen in
Journal of Cancer Research and Clinical Oncology / Ausgabe 10/2012
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-012-1253-8

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