Consistent expression of the stem cell renewal factor BMI‐1 in primary and metastatic melanoma

Abstract

Stem cell-like cells have recently been identified in melanoma cell lines, but their relevance for melanoma pathogenesis is controversial. To characterize the stem cell signature of melanoma, expression of stem cell markers BMI-1 and nestin was studied in 64 cutaneous melanomas, 165 melanoma metastases as well as 53 melanoma cell lines. Stem cell renewal factor BMI-1 is a transcriptional repressor of the Ink4a/Arf locus encoding p16 ink4a and p14Arf . Increased nuclear BMI-1 expression was detectable in 41 of 64 (64%) primary melanomas, 117 of 165 melanoma metastases (71%) and 15 of 53 (28%) melanoma cell lines. High nestin expression was observed in 14 of 56 primary melanomas (25%), 84 of 165 melanoma metastases (50%) and 21 of 53 melanoma cell lines (40%). There was a significant correlation between BMI-1 and nestin expression in cell lines (p 5 0.001) and metastases (p 5 0.02). These data indicate that cells in primary melanomas and their metastases may have stem cell properties. Cell lines obtained from melanoma metastases showed a significant higher BMI-1 expression compared to cell lines from primary melanoma (p 5 0.001). Further, primary melanoma lacking lymphatic metastases at presentation (pN0, n 5 40) was less frequently BMI-1 positive than melanomas presenting with lymphatic metastases (pN1; n 5 24; 52% versus 83%; p 5 0.01). Therefore, BMI-1 expression appears to induce a metastatic tendency. Because BMI-1 functions as a transcriptional repressor of the Ink4a/Arf locus, p16 ink4a and p14Arf expression was also analyzed. A high BMI-1/low p16 ink4a expression pattern was a significant predictor of metastasis by means of logistic regression analysis (p 5 0.005). This suggests that BMI-1 mediated repression of p16 ink4a may contribute to an increased aggressive behavior of stem cell-like melanoma cells. ' 2007 Wiley-Liss, Inc.

Sox10 promotes the formation and maintenance of giant congenital naevi and melanoma

“…S1a,b and Supplementary Table S1). Furthermore, extending studies by others 10-14 , we analyzed expression of SOX10 in a large set of human primary melanomas and melanoma metastases 15 . We found that the vast majority of all melanoma samples displayed nuclear SOX10 staining (Fig.…”

The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells

“…In humans, Bmi-1 plays an essential role in maintaining the self-renewal of normal and malignant human mammary stem cells (13). Meanwhile, Bmi-1 is also dysregulated in various human malignant neoplasms (14)(15)(16)(17)(18)(19). Previously, we reported that upregulation of Bmi-1 correlates with invasion of nasopharyngeal carcinomas (NPCs) and poor prognosis in patients (20).…”

The stem cell marker nestin predicts poor prognosis in human melanoma

“…Markers of melanocytic stem cells have been recently described (16,17), including nestin, an intermediate filament, which is expressed mainly in the cytoplasm of neuroepithelial stem cells (18,19) and in endothelium of growing blood vessels (20,21) but not in differentiated cells in parallel to loss of immunoreactivity to this protein (22). CD133 (human prominin-1/AC133), is another stem cell marker, a transmembrane glycoprotein that is expressed on hematopoietic stem cells, endothelial progenitor cells, and dermalderived stem cells capable of differentiating into neural cells (23,24).…”