microRNA-145 inhibits osteosarcoma cell proliferation and invasion by targeting ROCK1

Abstract

Abstract. Osteosarcoma (OS), a malignant mesenchymal sarcoma, is the most frequent primary bone tumor, with a peak incidence in young children and adolescents. The downregulation of microRNA-145 (miRNA/miR-145) has previously been identified to be associated with the aggressiveness and metastasis of OS. However, the detailed regulatory mechanism by which miR-145 inhibits OS remains largely unknown. The present study demonstrated that miR-145 was significantly downregulated in OS tissues and KHOS and U2OS cell lines. Rho-associated protein kinase 1 (ROCK1), a key regulator of actin cytoskeleton reorganization, was identified as a novel target of miR-145. Ectopic expression of miR-145 notably suppressed the protein expression of ROCK1 without affecting its mRNA level. Furthermore, the expression of ROCK1 was significantly increased in the OS tissues and in the KHOS and U2OS cells. It was further demonstrated that the overexpression of miR-145 downregulated KHOS and U2OS cell proliferation and invasion, which was reversed by restoration of ROCK1. To the best of our knowledge, the present study demonstrates for the first time that, as a tumor suppressor, miRNA-145 inhibits OS cell proliferation and invasion, at least in part by directly targeting ROCK1. These results indicate that miR-145 may be a potential candidate for the diagnosis and treatment of OS. IntroductionOsteosarcoma (OS) mainly arises from the metaphysis of the long bones of adolescents and young adults. OS is the most common primary malignant tumor and is associated with high morbidity (1). Despite wide tumor excision combining multi-agent chemotherapy and radiotherapy, the five-year survival rate of patients with recurrent or metastatic OS remains at ~30% (2). Although recent studies have focused on the molecular pathogenesis of OS (3), its detailed molecular mechanisms have not been fully elucidated. As a result, the identification of novel molecular candidates and/or targets is crucial for the development of effective therapeutic strategies to improve the prognosis of OS.microRNAs (miRNA/miRs) are small non-coding RNA molecules with 18-25 nucleotides, which mainly negatively regulate gene expression by suppressing translation via binding to the 3' untranslated region (3'UTR) of their target genes (4). Previously, miRNAs have been demonstrated to have crucial roles in various physiological and pathological processes, including the development and progression of malignant tumors (5). In fact, it has been demonstrated that miRNAs function as oncogenes or tumor suppressors in cellular proliferation, apoptosis, differentiation, migration and invasion in various cancer cells (6,7). Despite indications that several miRNAs, including miR-20a, miR-199a-3p, miR-143 and so forth, are involved in the development and progression of OS (8-10), their exact role remains largely unknown. Previously, miR-145 was identified as a tumor-suppressive miRNA in multiple types of cancers, including lung, glioma, ovarian, colon, gastric, bladder, prostate and breast cancer, ...

MicroRNA-144 acts as a tumor suppressor by targeting Rho-associated coiled-coil containing protein kinase 1 in osteosarcoma cells

“…These findings suggested that the inhibitory effect (12) reported that miR-340 suppressed osteosarcoma tumor growth and metastasis by directly targeting ROCK1 and Wang et al (22) revealed that miR-335 inhibited migration and invasion by targeting ROCK1 in osteosarcoma cells (22). In addition, miR-145 was demonstrated to inhibit osteosarcoma cell proliferation and invasion by targeting ROCK1 (23). The present study demonstrated that high expression of ROCK1 was inversely correlated with miR-144 expression, highlighting the role of miR-144 in the regulation of cell proliferation, migration and invasion by targeting ROCK1 in osteosarcoma cells.…”

Expression and clinical significance of cyclooxygenase-2 and microRNA-143 in osteosarcoma

“…Osteosarcoma is a highly malignant primary bone tumor, with bone-like tissue formed by tumor cells (1). As one of the early symptoms of osteosarcoma, patients experience intermittent pain, even prior to tumor formation.…”

“…Osteosarcoma is a highly malignant primary tumor occurring in the bone and associated tissues, characterized by a bone-like tissue consisting of tumor cells (1). As the disease progresses, osteosarcoma can progressively harm the health of the patients by causing lump formation, organ dysfunction and fractures (2)(3)(4).…”

Downregulation of microRNA-497 is associated with upregulation of synuclein γ in patients with osteosarcoma

“…Often occurring in the bones and skeleton or their auxiliary tissues, osteosarcoma displays characteristics of osteoid tissues directly formed by tumor cells (1). The majority of patients with osteosarcoma undergo amputation to remove the affected bone; however, post-amputation five-year survival rates remain low at 5%-20% (2).…”