Abstract
Because of the modest response rate after surgery and chemotherapy, treatment of osteosarcoma (OS) remains challenging due to tumor recurrence and metastasis. miR-135a has been reported to act as an anticarcinogenic regulator of several cancers. However, its expression and function in osteosarcoma remain largely unknown. Here, we reported that abridged miR-135a expression in OS cells and tissues, and its expression is inversely correlated with the expression of BMI1 and KLF4, which are described as oncogenes in several cancers. Ectopic expression of miR-135a inhibited cell invasion and expression of BMI1 and KLF4 in OS cells. In vivo investigation confirmed that miR-135a acts as a tumor suppressor in OS to inhibit tumor growth and lung metastasis in xenograft nude mice. BMI1 and KLF4 were revealed to be direct targets of miR-135a, and miR-135a had a similar effect as the combination of si-BMI1 and si-KLF4 on inhibiting tumor progression and the expression of BMI1 and KLF4 in vivo. Altogether, our results demonstrate that the targeting of BMI1/KLF4 with miR-135a may provide an applicable strategy for exploring novel therapeutic approaches for OS.
Highlights
Human osteosarcoma (OS), accounting for approximately 56% of bone sarcomas, is the most common malignant bone tumor and typically affects children, adolescents, and young adults with a median age of 16 years [1, 2]
We further examined expression miR-135a Reduces Osteosarcoma Lung Metastasis level of BMI1 and KLF4 in OS cell lines and normal bone cells using qRT-PCR, and expression level of BMI1, KLF4, and Ki67 in human OS samples using immunohistochemistry found that the BMI1 and KLF4 expressions were significantly higher in OS cell lines than in normal bone cells (**p < 0.01; Figure 1C) or higher in human OS samples than in nonmalignant bone samples (***p < 0.001; Figure 1D)
Mounting evidence supports the notion that aberrant BMI1 and KLF4 expression are responsible for tumor generation, metastasis, and treatment failure [10, 15, 17, 30]
Summary
Human osteosarcoma (OS), accounting for approximately 56% of bone sarcomas, is the most common malignant bone tumor and typically affects children, adolescents, and young adults with a median age of 16 years [1, 2]. OS is often diagnosed with lung metastasis at late stages due to its high proclivity for the local invasion and preferential metastasis to pulmonary parenchyma, in addition, recurrent disease is reported to be observed in 30%-50% of the population [2,3,4,5]. Around 68% of localized OS patients survive for five years or longer [8], but 20–30% suffer from metastatic or recurrent tumors [9]. Given the barriers to conventional treatment miR-135a Reduces Osteosarcoma Lung Metastasis methods, there is a crying need to establish novel therapeutic strategies that may improve the overall survival of OS
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