Clinical Value of Ezrin Expression in Primary Osteosarcoma
Chan KimEunah ShinSoojung HongHong Jae ChonHye Ryun KimJoong Bae AhnMin Hee HongWoo Ick YangJae Kyung RohSun Young Rha
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Ezrin is a membrane cytoskeletal linker protein and it is known to be associated with metastasis of primary osteosarcoma. The aim of this study is to determine the relationship between an ezrin expression and several key clinical parameters and to elucidate its potential prognostic value for patients with osteosarcoma.Seventy patients with histologically confirmed osteosarcoma and who had no distant metastasis were enrolled between 1995 and 2005 at Yonsei Cancer Center, Severance Hospital, Korea. The clinical parameters were retrospectively reviewed and immunohistochemical staining (IHC) for ezrin was performed using the surgically resected specimens.Of the 70 tumor specimens, 39 (55.7%) revealed an ezrin expression. More of an osteoblastic histology and an elevated initial ALP level were observed in the ezrin positive patients than in the ezrin negative patients (p=0.008 and 0.001, respectively). The proportion of patients who favorably responded to neoadjuvant chemotherapy (≥or=90% necrosis) was significantly higher in the group of ezrin positive patients than that in the group of ezrin negative patient (72.2% vs 45.2%, respectively, p=0.024). The ezrin positive patients showed more frequent recurrence than did the ezrin negative patients (64.1% vs 35.5%, respectively, p=0.017). The patients with an ezrin expression also demonstrated poorer survival than did those patients without ezrin expression (5-year EFS: 31.7% vs 61.3%, respectively, p=0.023, 5-year OS: 53.4% vs 71.0%, respectively, p=0.022). When comparing EFS according to both an ezrin expression and chemoresponsiveness, there were trends that the ezrin negative/chemoresponsive group showed the best 5-year EFS (71.4%), followed by the ezrin negative/chemoresistant group (52.9%), the ezrin positive/chemoresponsive group (38.1%) and the ezrin positive/chemoresistant group (13.6%). These trends were statistically significant (p=0.036).The expression of ezrin by IHC staining was found in 55.7% of the patients with metastasis-free osteosarcoma. Immunoreactivity to ezrin is a negative prognostic factor for survival for the patients suffering with osteosarcoma. Identifying an ezrin expression might offer a valuable piece of information when treating patients with primary osteosarcoma.The metastasis of osteosarcoma is a major threat to both adolescents and young adults. Identifying novel targets that may prevent osteosarcoma metastasis is critical in developing advanced clinical therapies for treating this cancer. The present study aimed to explore the mechanism of microRNA (miR)‑545‑5p in the metastasis of osteosarcoma. The present study identified miR‑545‑5p as a potential target that was downregulated in both osteosarcoma clinical samples and cell lines, and in the latter, ectopically expressed miR‑545‑5p caused apoptosis. In addition, miR‑545‑5p exerted inhibitory effects in osteosarcoma migration and invasion. Overexpression of miR‑545‑5p induced xenograft growth inhibition in vivo. In addition, miR‑545‑5p targeted dimethyladenosine transferase 1 (DIMT1), an oncogenic protein that facilitates osteosarcoma proliferation, migration and invasion. Taken together, the results of the present study suggest that miR‑545‑5p functions as a tumor suppressor in osteosarcoma that promotes apoptosis, while inhibiting migration and invasion by targeting DIMT1. Taken together, the results of the present study suggest two potential novel targets for osteosarcoma treatment and metastasis prevention.
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Gain-of-function of mutant p53 is associated with a high rate of lung metastasis in osteosarcoma. To investigate the mechanism of mutant p53-induced osteosarcoma metastasis, expression array analysis was performed, comparing non-metastatic osteosarcomas from p53+/- mice with metastatic osteosarcomas from p53R172H/+ mice. Onzin (Plac8) was identified as one of the genes upregulated in p53R172H/+ mouse metastatic osteosarcomas. Accordingly, we investigated the role of ONZIN in human osteosarcoma metastasis.ONZIN function and its downstream targets were examined in osteosarcoma cell lines. Assays related to tumorigenesis and metastasis, including cell migration, invasion, clonogenic survival, and soft agar colony formation, were performed in osteosarcoma cells. Additionally, mouse xenograft models were used to examine the role of ONZIN overpression in tumorigenesis in vivo. Lastly, 87 osteosarcoma patients were recruited to investigate the clinical relevance of ONZIN overexpression in metastasis and prognosis.ONZIN overexpression enhanced osteosarcoma cell proliferation, clonogenic survival, migration, and invasion independent of p53 status. Furthermore, ONZIN overexpression induced CXCL5 upregulation and resulted in increased ERK phosphorylation, which contributed to more aggressive osteosarcoma metastatic phenotypes. More importantly, overexpression of ONZIN in human osteosarcoma patients was closely associated with lung metastasis, poor prognoses, and survival.Overexpression of ONZIN promotes osteosarcoma progression and metastasis, and can serve as a clinical biomarker for osteosarcoma metastasis and prognosis.
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Osteosarcoma is a highly malignant solid tumor with poor prognosis, early metastasis, and rapid progression and has a high mortality rate, in which better therapeutic strategies are needed. Circ0038632, also known as circPLK1, is a tumor promotor in multiple cancers. However, its biological functions and molecular regulatory mechanisms in osteosarcoma remain unclear. To ascertain the function of circ0038632 in osteosarcoma, we checked its expression in cells and in tissues and tested its abilities of proliferation and migration. Expression experiment manifested that circ0038632 showed an enhanced expression in osteosarcoma. Functional studies revealed that circ0038632 inhibition reduced cell proliferation and metastasis abilities of osteosarcoma. Mechanism studies revealed that circ0038632 sponged miR-186 to upregulate the expression of DNA methyltransferase 3A (DNMT3A) to promote osteosarcoma progression. The circ0038632/miR-186/DNMT3A axis was involved in osteosarcoma progression. The results elucidated the potential application of circ0038632 as a novel diagnostic biomarker for progressive process of osteosarcoma.
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Abstract Osteosarcoma (OS), the most common primary cancer of bone, exhibits a high propensity for local invasion and distant metastasis. This study sought to elucidate the role of S phase kinase-associated protein (Skp2) in osteosarcoma invasion and metastasis and to explore flavokawain A (FKA), a natural chalcone from kava extract, as a potential Skp2 targeting agent for preventing osteosarcoma progression. Skp2 was found to be overexpressed in multiple osteosarcoma cell lines, including 5 standard and 8 primary patient-derived cell lines. Patients whose tumors expressed high levels of Skp2 sustained a significantly worse metastasis-free (p = 0.0095) and overall survival (p = 0.0013) than those with low Skp2. Skp2 knockdown markedly reduced in vitro cellular invasion and in vivo lung metastasis in an orthotopic mouse model of osteosarcoma. Similar to Skp2 knockdown, treatment with FKA also reduced Skp2 expression in osteosarcoma cell lines and blocked the invasion of osteosarcoma cells in vitro and lung metastasis in vivo . Together, our findings suggest that Skp2 is a promising therapeutic target in osteosarcoma, and that FKA may be an effective Skp2-targeted therapy to reduce osteosarcoma metastasis.
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Osteosarcoma is a malignant bone tumor that commonly occurs in the pediatric population. Despite the use of chemotherapy and surgery, metastasis remains to be the leading cause of death in patients with osteosarcoma. We have previously reported that cytoplasmic mislocalization of p27 is associated with a poor outcome in osteosarcoma. In this study, we further show that lysyl oxidase (LOX) expression was associated with p27 mislocalization. LOX is an enigmatic molecule that acts as a tumor suppressor or a metastatic promoter; however, its role in osteosarcoma is still unclear. Hence, we performed both in vitro and in vivo analyses to dissect the role of LOX in osteosarcoma. The result of our survival analysis indicated that LOX expression significantly correlated with a poor outcome in osteosarcoma with or without controlling for the initial metastasis status (P < 0.05). Functionally, we found that higher LOX expression promoted osteosarcoma cell proliferation, migration, and invasiveness in vitro and produced a higher number of mice with pulmonary metastases in an orthotopic xenograft mouse model. Mechanistically, phospho-FAK was increased in osteosarcoma cells with high LOX expression. Our results further showed that FAK inhibition significantly reduced tumor cell proliferation and migration in vitro as well as LOX-mediated metastasis in mice. Together, our findings suggest that there is a novel link between p27 mislocalization and LOX expression. LOX plays a pivotal role in osteosarcoma metastasis by upregulating FAK phosphorylation. FAK inhibition may constitute a promising therapeutic strategy to reduce the development of metastasis in osteosarcoma with LOX overexpression.
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ABSTRACT Nm23 protein expression was analyzed by immunohistochemical staining using formalin-fixed, paraffinembedded sections from 39 cases with osteosarcomas and compared with the histologic findings and early metastasis for the purpose of detecting nm23 expression in osteosarcoma and elucidating the clinical significance of its expression. Immunoreactivity of nm23 protein was detected in 48.7% of the total cases. There was no statistical difference between nm23 expression and early metastasis, but there was a trend for cases with nm23 expression to progress to early metastasis within 1 year after operation. The role of nm23 as a tumor metastasis suppressor in osteosarcomas appeared less prominent.
Metastasis Suppressor Gene
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Osteosarcoma is the most common primary malignancy of bone in teenagers and approximately 30% of patients develop lung metastasis, which is the leading cause of mortality. Recent studies suggest that the Ezrin protein is correlated with the metastatic potential of several malignant tumors. In our study, ectopic overexpression of miR-183 repressed the expression levels of Ezrin and significantly inhibited the motility and invasion of osteosarcoma cells. This suggests that miR-183 may possibly play a tumor suppressor role in the metastasis of osteosarcoma by downregulating Ezrin expression levels. These findings show that through inhibition of Ezrin expression levels, miR-183 is significantly involved in cell migration and invasion of osteosarcoma.
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To date, osteosarcoma metastasis genes, which are key for accurate initial diagnosis of the disease, have not been well identified. In the present study, osteosarcoma samples with and without metastasis were collected from 31 patients. Specific complementary DNA subtraction techniques were used to identify the osteosarcoma metastasis transcripts, which are responsible for the metastasis of osteosarcoma. The specific differentially expressed transcripts were identified by Basic Local Alignment Search Tool analysis and the results were validated by immunoblotting. Specifically, ezrin and β4 integrin were employed as markers to detect osteosarcoma metastasis in the initial stages. The results of the present study indicated that the two transcripts, ezrin and β4 integrin, were highly expressed in patients with osteosarcoma metastasis, and concluded that these were osteosarcoma metastasis genes. These results indicate that β4 integrin and/or ezrin may be used as a novel marker for the detection of osteosarcoma metastasis in the initial stages.
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