Abstract
NFATc1 is a transcription factor that regulates T-cell development, osteoclastogenesis, and macrophage function. Given that T cells, osteoclasts, and macrophages in the tumor microenvironment are thought to modulate tumor progression, tumor cells may acquire NFATc1 expression through fusion with these NFATc1-expressing normal cells. We here revealed that a small proportion of tumor cells in human carcinoma specimens expressed NFATc1. To investigate the consequences of NFATc1 acquisition by tumor cells, we established A549 and MCF7 cell lines expressing a constitutively active form of NFATc1 (NFATc1CA) in an inducible manner. The expression of NFATc1CA promoted cancer cell invasion in association with changes in cell morphology. Analysis of gene expression and RNA interference experiments revealed that NFATc1CA suppressed E-cadherin expression by upregulating the transcriptional repressors Snail and Zeb1 in a manner independent of TGF-β signaling. Induced expression of NFATc1CA also downregulated E-cadherin expression and increased invasive activity in tumor xenografts in vivo. Our results thus suggest that the acquisition of NFATc1 expression contributes to tumor progression.
Highlights
Tumor progression involves intricate interactions of tumor cells with a variety of nonmalignant cells in the tumor microenvironment
Morphologic and immunohistochemical examinations suggested that NFATc1expressing normal cells mostly consisted of CD68-positive macrophages (Fig. 2B)
Consistent with the notion that NFATc1CA expression induces epithelial–mesenchymal transition (EMT), we found that CDH1 expression was significantly downregulated by doxycycline treatment in both A549NFATc1CA and MCF7-NFATc1CA cells (Fig. 4A)
Summary
Tumor progression involves intricate interactions of tumor cells with a variety of nonmalignant cells in the tumor microenvironment. Recent evidence suggests that inflammation promotes the fusion of cardiomyocytes, skeletal muscle cells, hepatocytes, or Purkinje neurons with bone marrow-derived cells or lymphocytes in vivo [4, 5]. This fusion offers another potential mechanism (transfer of genetic material) by which normal cells might contribute to tumor progression. Macrophage–melanoma cell, osteoclast–myeloma cell, and macrophage, B-lymphocyte, or T-lymphocyte colon cancer cell hybrids have been detected in vivo [6,7,8,9]
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