Unknown,Transcriptomics,Genomics,Proteomics

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Expression profile of osteosarcoma cells in which Sox2 maintains cancer stem cells

ABSTRACT: Sox2 is required to maintain osteosarcoma cell tumor initiation.Knockdown of Sox2 leads tpo loss of tumorigenic properties. To examine gene expression changes upon Sox2 knockdown, we performed microarray analysis on mouse osteosarcoma cells expressing scrambled or Sox2shRNA. We found that genes upregulated upon Sox2 knockdown included osteoblast diffrentiation genes and genes down regulated included cell cycle and RNA processing genes as well as YAP-TEAD target genes. The Hippo pathway has a profound tumor suppressive role in cancer by restraining the strong growth-promoting function of YAP. We have previously shown that the stem cell transcription factor Sox2 maintains the tumorigenicity of osteosarcoma cancer stem cells (CSCs). In this report, we describe that Sox2 maintains stemness by antagonizing the Hippo pathway via direct repression of Hippo activators, Nf2 (Merlin) and WWC1 (Kibra), thereby leading to exaggerated YAP function. YAP is potently oncogenic in osteosarcoma and its depletion sharply reduces the tumorigenic CSC fraction. Low Nf2, low WWC1, and high YAP expression mark the CSC fraction of the tumor population, while the more differentiated fraction has high Nf2, high WWC1 and reduced YAP expression. This Sox2-Hippo axis is conserved and also operates in other Sox2-dependent cancers such as glioblastomas. We propose that disruption of YAP transcriptional activity reduces CSCs and could be a therapeutic strategy for Sox2- dependent tumors. Gene expression of 482 mouse lines mOS482 were analyzed by microarray. 3 replicates each of scrambled and Sox2shRNA were processed and hybridized

ORGANISM(S): Mus musculus

SUBMITTER: Alka Mansukhani

PROVIDER: E-GEOD-64965 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Object: The main limitation of treatment strategies for vestibular schwannomas (VSs) is loss of function of vestibulocochlear and facial nerves, which has driven investigations into new pharmaceutical therapies. The most common genetic alteration in human VSs is loss ofthe NF2 gene which encodes the protein merlin. It is well established that merlin achieves tumor suppressive functions through regulation of the Hippo pathway. The aim of this study was to analyze dysregulation of the Hippo pathway in sporadic VSs and to identify whether Hippo signaling could be potential targetable pathway for treatment of VS. Methods: In this study, we performed gene expression profiling of ten human sporadic VSs and four normal control vestibular nerves to identify aberrant expression of the Hippo pathway in VSs. Molecular subtypes in VSs was evaluated using unsupervised hierarchical clustering analysis. Western blot analysis and immunohistochemical staining were used to examine the expression of Hippo pathway core components in twenty human sporadic VSs. NF2 gene sequencing and mutation analysis were performed in all VS samples. Ki67 marker was used to investigate proliferation of tumor cells. Verteporfin was used to determine whether the inhibitor of YAP-TEAD reduced proliferation of human primary VS cells with NF2 mutations and RT4-D6P2T cell line. Results: We found fifty-one differentially expressed genes between VSs and controls. Unsupervised analysis of transcriptional profiles identified the two distinct molecular variants, which was significantly associated with NF2 mutation status. The protein level of MST2, LAST2,phospho-LAST1, and phospho-YAP were significantly decreased in VSs compared with normal tissues. Nuclear YAP staining was positively correlated with Ki-67 indexin VS samples. Finally, verteporfin reduced viability of human primary VS cells and in a dose-dependent manner by decreasing YAP expression. Conclusions: Our findings implicate that deregulation of the Hippo pathway as a molecular mechanism of pathogenesis in human sporadic VSs, and suggest inhibition of this pathway as a potential treatment strategy.

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Expression profile of osteosarcoma cells in which Sox2 maintains cancer stem cells

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