CCAAT/enhancer binding protein‐β promotes the survival of intravascular rat pancreatic tumor cells via antiapoptotic effects

A transcriptional factor, CCAAT/enhancer binding protein‐β (C/EBP‐β), regulates a variety of cell functions in normal and neoplastic cells. Although the involvement of C/EBP‐β in metastasis has been demonstrated clinicopathologically in several types of human cancer, the mechanism by which it functions during the multistep process of metastasis remains largely unknown. We investigated the role of C/EBP‐β in the intravascular step of hematogenous metastasis in a rat pancreatic tumor cell line, AR42J‐B13, as this step profoundly affects metastatic efficiency. C/EBP‐β‐transfected AR42J‐B13 (βB13) cells acquired considerable resistance against serum toxicity, which was primarily mediated by apoptosis in vitro. Upregulated expression of Bcl‐2 and Bcl‐xL was seen in βB13 cells. Enhanced early survival of intraportally injected βB13 cells in the BALB/c nu/nu male mice liver, detected by the mRNA of a vector‐specific gene, was observed. Nick‐end labeling analysis of the tumor‐injected liver revealed significantly lower rates of apoptosis among intravascular βB13 tumor cells than among empty vector‐transfected AR42J‐B13 (mB13) cells. Finally, intrasplenically injected βB13 cells established a larger number of colonies in the liver than did the mB13 cells. These findings suggest that C/EBP‐β may enhance hematogenous metastasis and its antiapoptotic effects may promote the survival of intravascular tumor cells. (Cancer Sci 2007; 98: 1706–1713)

[1]  D. Tosh,et al.  Expression of liver-enriched nuclear factors and their isoforms in alpha-fetoprotein-producing gastric carcinoma cells. , 2007, Experimental and molecular pathology.

[2]  M. Miyazaki,et al.  Dexamethasone modifies the susceptibility to serum cytotoxicity and increases the metastatic efficiency of a colon carcinoma cell line. , 2006, Experimental and molecular pathology.

[3]  D. Tosh,et al.  Characterization of liver function in transdifferentiated hepatocytes , 2006, Journal of cellular physiology.

[4]  John Calvin Reed,et al.  Increased expression of apoptosis inhibitor protein XIAP contributes to anoikis resistance of circulating human prostate cancer metastasis precursor cells. , 2005, Cancer research.

[5]  E. Kohn,et al.  Anoikis: Cancer and the homeless cell , 2004, Nature.

[6]  D. Peeper,et al.  Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB , 2004, Nature.

[7]  S. Takashiba,et al.  High Glucose Enhances Interleukin-6-induced Vascular Endothelial Growth Factor 165 Expression via Activation of Gp130-mediated p44/42 MAPK-CCAAT/Enhancer Binding Protein Signaling in Gingival Fibroblasts* , 2004, Journal of Biological Chemistry.

[8]  L. Boxer,et al.  Regulation of Bcl-2 expression by C/EBP in t(14;18) lymphoma cells , 2003, Oncogene.

[9]  K. Milde-Langosch,et al.  Expression of the CCAAT/Enhancer-Binding Proteins C/EBPα, C/EBPβ and C/EBPδ in Breast Cancer: Correlations with Clinicopathologic Parameters and Cell-Cycle Regulatory Proteins , 2003, Breast Cancer Research and Treatment.

[10]  M. Oya,et al.  Increased activation of CCAAT/enhancer binding protein-beta correlates with the invasiveness of renal cell carcinoma. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[11]  A. Welm,et al.  Calreticulin Interacts with C/EBPα and C/EBPβ mRNAs and Represses Translation of C/EBP Proteins , 2002, Molecular and Cellular Biology.

[12]  Mark W Dewhirst,et al.  Intravascular location of breast cancer cells after spontaneous metastasis to the lung. , 2002, The American journal of pathology.

[13]  David Tosh,et al.  Molecular basis of transdifferentiation of pancreas to liver , 2000, Nature Cell Biology.

[14]  A. Leutz,et al.  Translational control of C/EBPalpha and C/EBPbeta isoform expression. , 2000, Genes & development.

[15]  A. Welm,et al.  CUG repeat binding protein (CUGBP1) interacts with the 5'''' region of C/EBPβ β β β mRNA and regulates translation of C/EBPβ , 1999 .

[16]  S. Enerbäck,et al.  The expression of CCAAT/enhancer binding protein (C/EBP) in the human ovary in vivo: specific increase in C/EBPβ during epithelial tumour progression , 1999, British Journal of Cancer.

[17]  M. Takiguchi.  The C/EBP family of transcription factors in the liver and other organs , 1998, International journal of experimental pathology.

[18]  K. Luzzi,et al.  Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. , 1998, The American journal of pathology.

[19]  C. Zahnow,et al.  Overexpression of C/EBPβ-LIP, a Naturally Occurring, Dominant-Negative Transcription Factor, in Human Breast Cancer , 1997 .

[20]  S. Akira,et al.  Defective adipocyte differentiation in mice lacking the C/EBPβ and/or C/EBPδ gene , 1997 .

[21]  L. Tessarollo,et al.  An essential role for C/EBPbeta in female reproduction. , 1997, Genes & development.

[22]  T. Yoshiki,et al.  Gastrointestinal hepatoid adenocarcinoma: venous permeation and mimicry of hepatocellular carcinoma, a report of four cases , 1997, Histopathology.

[23]  L. Greenbaum,et al.  Coexistence of C/EBP alpha, beta, growth-induced proteins and DNA synthesis in hepatocytes during liver regeneration. Implications for maintenance of the differentiated state during liver growth. , 1995, The Journal of clinical investigation.

[24]  R. Cortese,et al.  Lymphoproliferative disorder and imbalanced T‐helper response in C/EBP beta‐deficient mice. , 1995, The EMBO journal.

[25]  Nobuaki Yoshida,et al.  Targeted disruption of the NF-IL6 gene discloses its essential role in bacteria killing and tumor cytotoxicity by macrophages , 1995, Cell.

[26]  S. McKnight,et al.  Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins. , 1995, Genes & development.

[27]  M. Tsuneyoshi,et al.  Hepatoid adenocarcinoma of the stomach. A clinicopathologic and immunohistochemical analysis , 1993, Cancer.

[28]  U. Schibler,et al.  A liver-enriched transcriptional activator protein, LAP, and a transcriptional inhibitory protein, LIP, are translated from the sam mRNA , 1991, Cell.

[29]  F. Belardelli,et al.  Host humoral and cellular immune mechanisms in the continued suppression of Friend erythroleukemia metastases after interferon alpha/beta treatment in mice , 1991, The Journal of experimental medicine.

[30]  S. Akira,et al.  A nuclear factor for IL‐6 expression (NF‐IL6) is a member of a C/EBP family. , 1990, The EMBO journal.

[31]  D. Dimitrov,et al.  The hemodynamic destruction of intravascular cancer cells in relation to myocardial metastasis. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[32]  D. Glaves.  Correlation between circulating cancer cells and incidence of metastases. , 1983, British Journal of Cancer.

[33]  R. Burton,et al.  Definitive evidence that natural killer (NK) cells inhibit experimental tumor metastases in vivo. , 1981, Journal of immunology.

[34]  Leonard Weiss.  Cancer cell traffic from the lungs to the liver: An example of metastatic inefficiency , 1980, International journal of cancer.

[35]  S. Chan,et al.  In vitro effects of lipoprotein-associated cytotoxic factor on rat prostate adenocarcinoma cells. , 1978, Cancer research.

[36]  Christopher W. Wong,et al.  Apoptosis: an early event in metastatic inefficiency. , 2001, Cancer research.

[37]  A. Al-Mehdi,et al.  Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis , 2000, Nature Medicine.

[38]  A. Leutz,et al.  Translational control of C/EBP (cid:1) and C/EBP (cid:2) isoform expression , 2000 .