This month’s featured article is from the lab of Wei Guo of Peking University People’s Hospital in Beijing, China. The article was published in the February 2017 issue of the journal Cell Death and Disease. This study focused on the mechanistic roles of long non-coding RNA HOTAIR in human chondrosarcoma. Chondrosarcoma is a bone tumor that is very deadly due to poor prognosis and high rates of recurrence. Little to no molecular therapies exist for the treatment of chondrosarcoma, so the development of a therapeutic is an unmet need in the bone cancer space.
The authors looked at HOTAIR expression in many chondrosarcoma tissue samples and cell lines. They found marked up-regulation of HOTAIR in all cancer samples relative to healthy controls, and also showed that high expression of HOTAIR was correlated with poor survivorship in chondrosarcoma patients. They further showed that HOTAIR knockdown led to growth arrest of chondrosarcoma cells and apoptosis.
Next, they sought to find the mechanism underlying HOTAIR-mediated chondrosarcoma cell growth. To this end, they used Phalanx Biotech’s Human miRNA OneArray Microarray to determine miRNAs regulated by HOTAIR. They found 25 up-regulated miRNAs in a cell line transfected with a siRNA that down-regulates HOTAIR (see the above heat map). One of the up-regulated miRNAs was miR-454-3p, and the authors chose to focus further experiments on miR-454-3p because it was down-regulated in those same cell lines and tissue samples that had elevated HOTAIR expression. In all experiments performed, a significant inverse relationship was found between HOTAIR and miR-454-3p expression. Lastly, the authors further elucidated the mechanism by showing that miR-454-3p expression was epigenetically controlled by HOTAIR and EZH2, and that Stat3 and Atg12 were targets of miR-454-3p that mediated the reduction of chrondrosarcoma growth.
In summary, the authors revealed a mechanism by which HOTAIR, miR-454-3p, and its targets are responsible for chondrosarcoma growth and thereby patient survival. This pathway represents an exciting new avenue for further research, and it holds great potential as a target for chondrosarcoma therapeutics.
Bao X et al. Knockdown of long non-coding RNA HOTAIR increases miR-454-3p by targeting Stat3 and Atg12 to inhibit chondrosarcoma growth (2017). Cell Death Dis 8(2):e2605.