Abstract
Previous studies have shown that Meis1 plays an important role in the pathogenesis of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Meis1 belongs to the TALE family, the members of which are used as biomarkers for AML. Meis1 has been shown to play a functional role in epithelial tissues, such as skin. However, its functions in skin carcinogenesis remain poorly understood. On the other hand, the c-Met inhibitor SU11274 has been identified through drug screening with HOXA9/Meis1-induced AML cell lines. SU11274 altered cell proliferation and the cell cycle status in human AML cell lines. Thus, we hypothesized that the effects of SU11274 are dependent on Meis1 and that its knockdown may diminish the effects of SU11274 not only in AML cell lines, but also in skin cancer cell lines. In order to test our hypothesis, we established Meis1 knockdown cell lines using two skin squamous cell carcinoma cell lines (B9 and D3) and treated these cell lines with SU11274. The results obtained showed that SU11274 suppressed cell proliferation by modulating cell cycle progression in the presence of Meis1, but not in its absence. Furthermore, an expression analysis showed that SU11274 activated the transcription of Meis1, which led to the transcription of Hif1α and Cdkn2a (p16Ink4a and p19Arf). These results suggest that Meis1 is required for the c-Met inhibitor SU11274 to suppress the proliferation of the skin squamous cell carcinoma cell lines.
Highlights
Meis1 is a member of the TALE family of homeodomain transcription factors, which interact with Hox transcription factors and promote the expression of their target genes [1]-[3]
Gene expression studies in lung adenocarcinomas [10], neuroblastomas [11]-[13], ovarian carcinomas [14], and nephroblastomas [15] have shown that the expression of Meis1 is up-regulated in tumor tissues, which is suggestive of an oncogenic role
This study shows Meis1 is required for the c-Met inhibitor SU11274 to suppress the proliferation of the skin squamous cell carcinoma cell lines B9 and D3
Summary
Meis (myeloid ecotropic insertion site 1) is a member of the TALE (three amino acid loop extension) family of homeodomain transcription factors, which interact with Hox transcription factors and promote the expression of their target genes [1]-[3]. These interactions functionally incorporate Meis into a range of Hox-dependent developmental programs [4]. Several studies have suggested that Meis plays a functional role in several tissues, such as hematopoietic stem cells (HSCs) [17], cardiomyocytes [18], lung cancer cell lines [19], thymus [20] and skin [16]. These findings suggest that Meis exerts anti-proliferative effects as well as oncogenic activities, and has complex roles in cell proliferation, which may depend on the cellular context
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