Breast cancer suppressor candidate-1 (BCSC-1) is a melanoma tumor suppressor that down regulates MITF

Understanding the molecular aberrations involved in the development and progression of metastatic melanoma (MM) is essential for a better diagnosis and targeted therapy. We identified breast cancer suppressor candidate-1 (BCSC-1) as a novel tumor suppressor in melanoma. BCSC-1 expression is decreased in human MM, and its ectopic expression in MM-derived cell lines blocks tumor formation in vivo and melanoma cell proliferation in vitro while increasing cell migration. We demonstrate that BCSC-1 binds to Sox10, which down regulates MITF, and results in a switch of melanoma cells from a proliferative to a migratory phenotype. In conclusion, we have identified BCSC-1 as a tumor suppressor in melanoma and as a novel regulator of the MITF pathway.     

NPR-A regulates self-renewal and pluripotency of embryonic stem cells

Self-renewal and pluripotency of embryonic stem (ES) cells are maintained by several signaling cascades and by expression of intrinsic factors, such as Oct4, Nanog and Sox2. The mechanism regulating these signaling cascades in ES cells is of great interest. Recently, we have demonstrated that natriuretic peptide receptor A (NPR-A), a specific receptor for atrial and brain natriuretic peptides (ANP and BNP, respectively), is expressed in pre-implantation embryos and in ES cells. Here, we examined whether NPR-A is involved in the maintenance of ES cell pluripotency. RNA interference-mediated knockdown of NPR-A resulted in phenotypic changes, indicative of differentiation, downregulation of pluripotency factors (such as Oct4, Nanog and Sox2) and upregulation of differentiation genes. NPR-A knockdown also resulted in a marked downregulation of phosphorylated Akt. Furthermore, NPR-A knockdown induced accumulation of ES cells in the G1 phase of the cell cycle. Interestingly, we found that ANP was expressed in self-renewing ES cells, whereas its level was reduced after ES cell differentiation. Treatment of ES cells with ANP upregulated the expression of Oct4, Nanog and phosphorylated Akt, and this upregulation depended on NPR-A signaling, because it was completely reversed by pretreatment with either an NPR-A antagonist or a cGMP-dependent protein kinase inhibitor. These findings provide a novel role for NPR-A in the maintenance of self-renewal and pluripotency of ES cells.     

A proliferative melanoma cell phenotype is responsive to RAF/MEK inhibition independent of BRAF mutation status

Oncogenic mutations within the MAPK pathway are frequent in melanoma, and targeting of MAPK signaling has yielded spectacular responses in a significant number of patients that last for several months before relapsing. We investigated the effects of two different inhibitors of MAPK signaling in proliferative and invasive melanoma cell cultures with various mutations in the MAPK pathway. Proliferative melanoma cells were more susceptible to pathway inhibition than invasive phenotype cells, irrespective of BRAF mutation status, while invasive phenotype cell response was dependent on BRAF mutation status. Critically, MAPK pathway inhibition of proliferative phenotype cells resulted in acquisition of invasive phenotype characteristics. These results show that melanoma cell phenotype is an important factor in MAPK pathway inhibition response. This suggests that while current therapeutic strategies target proliferative melanoma cells, future approaches should also account for the invasive phenotype population.     

Id2 suppression of p15 counters TGF‐β‐mediated growth inhibition of melanoma cells

Proliferative resistance to transforming growth factor β (TGF‐β) is regarded as a critical turning point in the malignant progression of many cancer types. In melanoma this resistance is associated with more aggressive metastatic behaviour. A recent study by our group identified proliferative and invasive subtypes of melanoma cultures and found that these are, respectively, susceptible and resistant to TGF‐β suppression of proliferation. Here, using previously characterised proliferative and invasive phenotype melanoma cultures, we explored molecular responses involved in modulating susceptibility to TGF‐β‐mediated inhibition of proliferation. The Id2 gene was identified as being expressed more strongly in invasive phenotype cells less susceptible to TGF‐β repression than in proliferative phenotype cells. We correlated TGF‐β repression of Id2 gene expression in proliferative phenotype cells with p15^Ink4b induction and cell cycle arrest. Furthermore, ectopic Id2 expression in proliferative phenotype cells counteracted p15^Ink4b induction and consequently protected them from TGF‐β‐mediated inhibition of proliferation. We conclude that transition to increased aggressiveness in melanoma cells requires Id2 upregulation to suppress TGF‐β induction of p15^Ink4b and thus help to circumvent TGF‐β‐mediated inhibition of proliferation.