Hypoxia-induced let-7f-5p/TARBP2 feedback loop regulates osteosarcoma cell proliferation and invasion by inhibiting the Wnt signaling pathway.

Guangnan Chen,Kaifeng Zhou,Jun Xu,Huijie Gu,Tingting Fang,Xiaofan Yin

doi:10.18632/aging.103049

Abstract

Osteosarcoma (OS) is the most common bone tumor in children and adolescents and is characterized by high metastatic and recurrence rates. In the past, it has been shown that microRNAs may play critical roles in hypoxia-related OS proliferation and invasion. However, the mechanisms by which OS cells acquire this malignant phenotype have remained largely unknown. In the present study, we report that let-7f-5p and TARBP2 were expressed in lower amounts in human OS cell lines when compared with the hFOB normal human osteoblastic cell line; however, both types of cells were repressed by hypoxia. let-7f-5p and TARBP2 significantly inhibited the proliferation and invasion of OS cells. Furthermore, TARBP2 as a downstream and functional target of let-7f-5p regulated the expression of let-7f-5p, and there was a regulatory feedback loop between let-7f-5p and TARBP2. This loop reduced the expression of let-7f-5p and TARBP2 in OS cells to a very low level, which was induced by hypoxia. Furthermore, the hypoxia-induced let-7f-5p/TARBP2 feedback loop contributed to activation of the Wnt signaling pathway. Taken together, our data clearly showed that the feedback loop between let-7f-5p and TARBP2 induced by the hypoxia-promoted OS cell malignant phenotype increased with activation of the Wnt signaling pathway.

Highlights

Osteosarcoma (OS) is the most common primary bone cancer and the third most common cancer, occurring predominantly in children and adolescents; it is characterized by rapid growth, and is highly prone to metastasis and recurrence [1, 2]
We report that let-7f-5p and RNA-induced silencing complex (RISC) loading complex RNA binding subunit (TARBP2) were expressed in lower amounts in human OS cell lines when compared with the hFOB normal human osteoblastic cell line; both types of cells were repressed by hypoxia. let-7f-5p and TARBP2 significantly inhibited the proliferation and invasion of OS cells
We focused on let-7f-5p and identified a regulatory feedback loop between TARBP2 and let-7f5p, which could result in proliferation and invasion in OS, depending on the context of cellular hypoxia

Summary

INTRODUCTION

Osteosarcoma (OS) is the most common primary bone cancer and the third most common cancer, occurring predominantly in children and adolescents; it is characterized by rapid growth, and is highly prone to metastasis and recurrence [1, 2]. MicroRNAs (miRNAs) are a class of non-coding RNAs of approximately 22 nucleotides in length that normally mediate post-transcriptional gene suppression www.aging-us.com by inhibiting protein translation or cleavage of RNA transcripts in a sequence-specific manner They play an important role in many biological processes such as development and cell differentiation, apoptosis, proliferation, and senescence [7, 8]. MiRNAs frequently form feedback circuits [7, 18], because they are themselves regulated by genes, which they directly or indirectly target Such self-stabilizing regulatory loop destructions can be central components of epigenetic switches, and serve crucial functions in the process of tumor genesis and metastasis [19, 20]. We focused on let-7f-5p and identified a regulatory feedback loop between TARBP2 and let-7f5p, which could result in proliferation and invasion in OS, depending on the context of cellular hypoxia

RESULTS

DISCUSSION

MATERIALS AND METHODS