microRNA-222-Mediated VHL Downregulation Facilitates Retinoblastoma Chemoresistance by Increasing HIF1α Expression

Abstract

PURPOSE. Retinoblastoma (RB) is the most common primary intraocular tumor in children. Chemoresistance is the major obstacle for treatment of these tumors. This study aims to determine whether or not downregulating microRNA-222 (miR-222) could serve as a potential therapeutic target for preventing chemoresistance in RB treatment. METHODS. Differentially expressed miR-222 in RB samples and its downstream target genes were predicted using bioinformatics methods. The expression of miR-222 was altered by mimic or inhibitor to examine its role in RB cell in response to the chemotherapeutic agent vincristine (VCR). Further bioinformatic analysis predicted involvement of the stability of hypoxia-inducible factor 1α (HIF1α) protein in regulation of the von Hippel-Lindau (VHL) tumor suppressor, followed by characterization of the effect of VHL on the ubiquitin-proteasome degradation of HIF1α. Next, VHL or HIF1α was overexpressed to determine their effects on RB cell activities after VCR treatment. In vivo assays were performed on nude mice to further verify the in vitro results. RESULTS. miR-222 is highly expressed in RB tissues and cells and was found to facilitate resistance of RB cells to VCR. Of note, miR-222 specifically bound to and negatively regulated VHL. VHL could inhibit the stability of HIF1α and promote the degradation of ubiquitin-proteasome, thus reducing HIF1α expression to attenuate VCR resistance in RB cells. Moreover, inhibition of miR-222 in combination with VCR suppressed tumor formation in nude mice. CONCLUSIONS. miR-222 promotes the expression of HIF1α by targeting VHL, thus accelerating the resistance of RB cells to the chemotherapeutic agent VCR.

LncRNA MIR17HG promotes the proliferation, migration, and invasion of retinoblastoma cells by up‐regulating HIF‐1α expression via sponging miR‐155‐5p

“…This is reasonable since HIF-1α is also detectable under normoxia in tumor tissues. 20,[36][37][38] In the following studies, the role of MIR17HG/miR-155-5p/HIF-1α in RB in hypoxic microenvironment should be further investigated.…”

Extracellular vesicles-derived microRNA-222 promotes immune escape via interacting with ATF3 to regulate AKT1 transcription in colorectal cancer

“…As regards to the function of miR-222, increased miR-222-3p expression was associated with metastasis and a poor prognosis in renal clear cell carcinoma [19]. In addition, miR-222 was enriched in retinoblastoma tissues and cells, which facilitated resistance of retinoblastoma cells to vincristine, a chemotherapeutic agent [20]. Under the context of CRC, HCT116 and SW480 cells illustrated repressed invasion and migration abilities and enhanced apoptosis in response to miR-222-3p inhibitor [21].…”

microRNAs in cancer chemoresistance: The sword and the shield

“…Overexpression of miR-222 was found to inhibit VHL, a protein that forms part of the VHL E3 ubiquitin ligase complex, which helps in the ubiquitination and degradation of unwanted proteins. Inhibition of VHL was correlated with increased HIF-1α stability, further increasing vincristine resistance in retinoblastoma cells [ 87 ]. Moreover, hypoxia was found to induce EMT and increase 5-FU resistance in p53 (tumor suppressor) mutant or deficient CRC via downregulation of miR-34a.…”