miR-367 as a therapeutic target in stem-like cells from embryonal central nervous system tumors

Author(s)

Kaid, Carolini ^[1] ; Jordan, Dione ^[1] ; de Siqueira Buenos, Heloisa Maria ^[1] ; Silva Araujo, Bruno Henrique ^[2] ; Assoni, Amanda ^[1] ; Okamoto, Oswaldo Keith ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Biociencias, Dept Genet & Biol Evolut, Ctr Pesquisa Genoma Humano & Celulas Tronco, Rua Matao 277, BR-05508090 Sao Paulo, SP - Brazil

^[2] Brazilian Ctr Res Energy & Mat CNPEM, Brazilian Biosci Natl Lab LNBio, Campinas, SP - Brazil

• Document type: Journal article
• Source: MOLECULAR ONCOLOGY; v. 13, n. 12 AUG 2019.
• Web of Science Citations: 0

Abstract

Aberrant expression of the pluripotency factor OCT4A in embryonal tumors of the central nervous system (CNS) is a key factor that contributes to tumor aggressiveness and correlates with poor patient survival. OCT4A overexpression has been shown to up-regulate miR-367, a microRNA (miRNA) that regulates pluripotency in embryonic stem cells and stem-like aggressive traits in cancer cells. Here, we show that (a) miR-367 is carried in microvesicles derived from embryonal CNS tumor cells expressing OCT4A; and (b) inhibition of miR-367 in these cells attenuates their aggressive traits. miR-367 silencing in OCT4A-overexpressing tumor cells significantly reduced their proliferative and invasive behavior, clonogenic activity, and tumorsphere generation capability. In vivo, targeting of miR-367 through direct injections of a specific inhibitor into the cerebrospinal fluid of Balb/C nude mice bearing OCT4A-overexpressing tumor xenografts inhibited tumor development and improved overall survival. miR-367 was also shown to target SUZ12, one of the core components of the polycomb repressive complex 2 known to be involved in epigenetic silencing of pluripotency-related genes, including POU5F1, which encodes OCT4A. Our findings reveal possible clinical applications of a cancer stemness pathway, highlighting miR-367 as a putative liquid biopsy biomarker that could be further explored to improve early diagnosis and prognosis prediction, and potentially serve as a therapeutic target in aggressive embryonal CNS tumors. (AU)

• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 13/02983-1 - Expression of hsa-miR-367 and aggressiveness of human medulloblastoma
• Grantee: Carolini Kaid Dávila
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 16/09707-8 - Interaction between the protein VAPB and the development of embryonic tumors on the central nervous system
• Grantee: Amanda Faria Assoni
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/08049-1 - The role of astrocytes in the synaptic plasticity of neurons derived from induced pluripotent stem cells from Down Syndrome patients
• Grantee: Bruno Henrique Silva Araujo Torres
• Support Opportunities: Scholarships in Brazil - Post-Doctoral