Prominent role of RAB39A-RXRB axis in cancer development and stemness
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Tokuhiro Chano1, Hiroko Kita1, Sofia Avnet2, Silvia Lemma2 and Nicola Baldini2,3
1Department of Clinical Laboratory Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
2Orthopaedic Pathophysiology and Regenerative Medicine Unit, Istituto Ortopedico Rizzoli, Bologna, Italy
3Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
Tokuhiro Chano, email: [email protected]
Keywords: RAB39A; RXRB; cancer stem cell; spherogenicity; tumorigenesis
Received: September 19, 2017 Accepted: November 16, 2017 Published: January 04, 2018
In this study, we found that RAB39A, a member of the RAS oncogene family, was selectively expressed in cancer cells of different histotypes, by analyzing gene expression in human osteosarcoma cells and the cancer stem cells (CSCs) and by comparing them with normal cells through global transcriptomics and principal component analyses. We further validated RAB39A as a therapeutic target, by silencing its expression. The silencing impaired cancer stemness and spherogenic ability in vitro, as well as tumorigenesis in vivo. RNA-seq analyses in the silenced spheres suggested that RAB39A is associated downstream with RXRB and KLF4. Notably, RXRB expression was inhibited in RAB39A-silenced CSCs. Induced overexpression of RXRB in RAB39A-silenced cells restored spherogenic ability and tumorigenesis, confirming RXRB as a major effector of RAB39A. Quantitative RT-PCR analysis of ~400 human cancer tissues showed that RAB39A was highly expressed in sarcomas and in malignancies of lymphoid, adrenal and testicular tissues. Our data provide the rationale for targeting of the RAB39A-RXRB axis as a therapy for aggressive cancers.
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