piR-39980 promotes cell proliferation, migration and invasion, and inhibits apoptosis via repression of SERPINB1 in human osteosarcoma.

Piwi-interacting RNAs (piRNAs) are a novel class of ∼23-36 nts long endogenous small non-coding RNAs, earlier known to maintain germline genome integrity during development by regulating transposable elements. Recently, piRNAs are known to regulate cell proliferation, apoptosis and metastasis in different cancer cells. However, piRNAs have not yet been reported in human osteosarcoma (OS), a highly metastatic aggressive bone tumour among adolescents. Therefore, our current study aimed to decrypt the potential role of a piRNA, piR-39980 in osteosarcoma, which was earlier reported by us in fibrosarcoma, neuroblastoma and epithelial ovarian cancer. We found that piR-39980 is significantly upregulated in two human osteosarcoma cell lines, 143B and HOS compared to IMR90-tert fibroblast cells. The transient overexpression of endogenous piR-39980 level through transfection by piRNA mimic promotes proliferation, migration and invasion ability of OS cells, whereas its inhibition significantly induces apoptosis, chromatin condensation and γ-H2AX accumulation as well as restrains migration and invasion of OS cells. Further, we found 13 genes as targets of piR-39980 using miRanda, among which SERPINB1 that is downregulated in OS cells is seen to suppress proliferation, and migration in this cancer upon its overexpression. The knockdown of piR-39980 in OS cells led to enhanced expression of SERPINB1 indicating to be its target, which was then confirmed by dual luciferase reporter assay. In addition, gelatin zymography and western blotting revealed that transfection of piR-39980 mimic promotes MMP-2 activation, whereas its inhibition and SERPINB1 overexpression suppresses MMP-2 activation in OS cells. Taken together, our study revealed that piR-39980 promotes migration and invasion via MMP-2 activation as well as inhibits cell death, both through negative regulation of SERPINB1. This study revealed that piR-39980 functions as an oncogene in human osteosarcoma, which could be harnessed as a potential therapeutic target for this malignancy.