The leukemia inhibitory factor (LIF) and p21 mediate the TGFβ tumor suppressive effects in human cutaneous melanoma

Abstract

BackgroundCutaneous melanoma is the most lethal skin cancer and its incidence in developed countries has dramatically increased over the past decades. Localized tumors are easily treated by surgery, but advanced melanomas lack efficient treatment and are associated with very poor outcomes. Thus, understanding the processes underlying melanoma development and progression is critical. The Transforming Growth Factor beta (TGFβ) acts as a potent tumor suppressor in human melanoma, by inhibiting cell growth and preventing cellular migration and invasion.MethodsIn this study, we aimed at elucidating the molecular mechanisms underlying TGFβ-mediated tumor suppression. Human cutaneous melanoma cell lines, derived from different patients, were used to assess for cell cycle analysis, apoptosis/caspase activity and cell migration. Techniques involved immunoblotting, immunohistochemistry, real time PCR and luciferase reporter assays.ResultsWe found the leukemia inhibitory factor (LIF) to be strongly up-regulated by TGFβ in melanoma cells, defining LIF as a novel TGFβ downstream target gene in cutaneous melanoma. Interestingly, we also showed that TGFβ-mediated LIF expression is required for TGFβ-induced cell cycle arrest and caspase-mediated apoptosis, as well as for TGFβ-mediated inhibition of cell migration. Moreover, we found that TGFβ-mediated LIF expression leads to activation of transcription of the cell cycle inhibitor p21 in a STAT3-dependent manner, and further showed that p21 is required for TGFβ/LIF-mediated cell cycle arrest and TGFβ-induced gene activation of several pro-apoptotic genes.ConclusionsTogether, our results define the LIF/p21 signaling cascade as a novel tumor suppressive-like pathway in melanoma, acting downstream of TGFβ to regulate cell cycle arrest and cell death, further highlight new potential therapeutic strategies for the treatment of cutaneous melanoma.

Involvement of oncogenic tyrosine kinase NPM-ALK in trifluoperazine-induced cell cycle arrest and apoptosis in ALK+ anaplastic large cell lymphoma

“…We cannot exclude the possibility that the decreased levels of STAT3 were mediated by the degradation of NPM-ALK induced by TFP. Additionally, the cell cycle regulatory proteins p21, p27, and CDK2 are directly regulated by STAT3 [26][27][28]. Our data demonstrated that the cell cycle arrest induced by TFP was related to the degradation of STAT3.…”

p53 and miR‐210 regulated NeuroD2, a neuronal basic helix–loop–helix transcription factor, is downregulated in glioblastoma patients and functions as a tumor suppressor under hypoxic microenvironment

“…The dissection of the molecular mechanisms underlying various functions of NeuroD2 was done through documentation of its targets. NeuroD2 was found to upregulate transcript levels of IL‐24, BMP2 and LIF . Interestingly, previous reports of these factors show cancer specific growth suppressing and apoptosis inducing properties.…”

“…NeuroD2 was found to upregulate transcript levels of IL-24, BMP2 and LIF. [24][25][26] Interestingly, previous reports of these factors show cancer specific growth suppressing and apoptosis inducing properties. NeuroD2 also suppresses the expression of proinflammatory cytokines such as CXCL8 and IL6 whereas increases the level of others such as CXCL5 and IL1B.…”

Ecotropic viral integration site 1 regulates the progression of acute myeloid leukemia via MS4A3‑mediated TGFβ/EMT signaling pathway

“…The TGFβ/EMT signaling pathway serves a crucial role in mediating tumor suppressive effects in human cutaneous melanoma (20). TGFβ-mediated formation of retinoblastoma protein-E2F complexes has been demonstrated to be involved in the proliferation and invasion of human myeloid leukemia cells (29).…”