Biomarker For Prognosis In Osteosarcoma Research Articles

Hypermethylated PODN represses the progression of osteosarcoma by inactivating the TGF-β/Smad2/3 pathway

BackgroundPODN is reported to be an promising biomarker for prognosis of osteosarcoma (OS), while the specific function of PODN has not been explored in OS. This study is designed to explore the function and underlying mechanism of PODN in OS. MethodsThe mRNA expression of PODN was determined using qRT-PCR. Protein levels of PODN, DNMT1, DNMT3A, DNMT3B, TGF-β1, Smad2/3 and p-Smad2/3 were detected using western blot. The methylation of PODN was determined with methylation-specific PCR. Moreover, CCK-8 assay and colony formation assay were used for assessing the proliferation of OS cells. Transwell assay was used to evaluate migration and invasion abilities of OS cells. Immunohistochemical staining was performed to determine the protein expression of Ki67 and PODN in tumor tissues. For constructing a xenograft tumor model, MG-63 cells were introduced into the right side of the mouse back via subcutaneous injection. ResultsPODN was lowly expressed and was hypermethylated in OS tissues and cells. PODN overexpression prevented OS cells from proliferating, migrating and invading, and inhibited tumorigenesis in xenograft mice. After PODN overexpression, protein levels of TGF-β1 and p-Smad2/3 were decreased in OS cells. Meantime, the suppressive effects of PODN overexpression on proliferation, migration and invasion of OS cells as well as mouse tumorigenesis were partly counteracted by TGF-β1 overexpression. ConclusionsPODN overexpression inactivated the TGF-β/Smad2/3 pathway to suppress OS development in vitro and in vivo.

Blocking circ-CNST suppresses malignant behaviors of osteosarcoma cells and inhibits glycolysis through circ-CNST-miR-578-LDHA/PDK1 ceRNA networks

BackgroundCircRNA CNST (circ-CNST) is a newly identified biomarker for prognosis of osteosarcoma (OS). However, its role in OS progression remains to be well documented.MethodsExpression of circ-CNST, microRNA (miR)-578, lactate dehydrogenase A (LDHA), and pyruvate dehydrogenase kinase 1 (PDK1) was detected by quantitative real-time polymerase chain reaction and Western blotting. The physical interaction was confirmed by dual-luciferase reporter assay. Cell behaviors and glycolysis were measured by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay, colony formation assay, flow cytometry, transwell assays, xenograft experiment, and commercial kits.ResultsCirc-CNST was upregulated in human OS tissues and cells, accompanied with downregulation of miR-578 and upregulation of LDHA and PDK1. There were negative correlations between miR-578 expression and circ-CNST or LDHA/PDK1 in OS tissues. Moreover, high circ-CNST/LDHA/PDK1 or low miR-578 might predict shorter overall survival, advanced TNM stages, and lymph node metastasis. Physically, miR-578 was targeted by circ-CNST, and miR-578 could target LDHA/PDK1. Functionally, blocking circ-CNST and restoring miR-578 enhanced apoptosis rate and suppressed cell proliferation, colony formation, migration, and invasion in 143B and U2OS cells, accompanied with decreased glucose consumption, lactate production, and adenosine triphosphate (ATP)/adenosine diphosphate (ADP) ratio. Furthermore, in vivo growth of U2OS cells was retarded by silencing circ-CNST. Depletion of miR-578 could counteract the suppressive role of circ-CNST deficiency in 143B and U2OS cells, and restoring LDHA or PDK1 partially reversed the role of miR-578 inhibition as well.ConclusionCirc-CNST knockdown could antagonize malignant behaviors and glycolysis of OS cells by regulating miR-578-LDHA/PDK1 axes.

Circular RNA circ-NT5C2 acts as a potential novel biomarker for prognosis of osteosarcoma.

We detected some serious inaccuracies and mistakes. Therefore, the article, "Circular RNA circ-NT5C2 acts as a potential novel biomarker for prognosis of osteosarcoma, by W.-B. Nie, L.-M. Zhao, R. Guo, M.-X. Wang, F.-G. Ye, published in Eur Rev Med Pharmacol Sci 2018; 22 (19): 6239-6244-DOI: 10.26355/eurrev_201810_16030-PMID: 30338784" has been withdrawn. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/16030.

Circular RNA hsa_circ_0002052 promotes osteosarcoma via modulating miR-382/STX6 axis.

Circular RNAs (circRNAs) exert pivotal effects on regulating the progression of osteosarcoma (OS). It was found through microarray analysis that circ-0002052 is abnormally expressed in OS, but the role of circ-0002052 in OS remains obscure. The results of this research manifested that relative to that in non-tumor controls, circ-0002052 level was raised in OS tissues. Up-regulated circ-0002052 was associated with advanced stage, tumor size, and metastasis. Additionally, circ-0002052 elevation indicated a low survival rate in OS patients and silencing of circ-0002052 suppressed proliferation, migration, and invasion of OS cells. It was proved that circ-0002052 sponged miR-382 and stimulated STX6 expression, thus activating Wnt/β-catenin. The function of circ-0002052 reduction in OS cells was effectively reversed by miR-382 suppression. To sum up, it can be concluded that circ-0002052, functioning as a sponge for miR-382, enhances the activation of Wnt/β-catenin mediated by STX6 to stimulate the progression of OS, and circ-0002052 may be an underlying treatment target and a biomarker for prognosis of osteosarcoma.

CDKL3 promotes osteosarcoma progression by activating Akt/PKB.

Osteosarcoma (OS) is a primary malignant bone neoplasm with high frequencies of tumor metastasis and recurrence. Although the Akt/PKB signaling pathway is known to play key roles in tumorigenesis, the roles of cyclin-dependent kinase-like 3 (CDKL3) in OS progression remain largely elusive. We have demonstrated the high expression levels of CDKL3 in OS human specimens and comprehensively investigated the role of CDKL3 in promoting OS progression both in vitro and in vivo. We found that CDKL3 regulates Akt activation and its downstream effects, including cell growth and autophagy. The up-regulation of CDKL3 in OS specimens appeared to be associated with Akt activation and shorter overall patient survival (P = 0.003). Our findings identify CDKL3 as a critical regulator that stimulates OS progression by enhancing Akt activation. CDKL3 represents both a biomarker for OS prognosis, and a potential therapeutic target in precision medicine by targeting CDKL3 to treat Akt hyper-activated OS.

A commentary on “Long non-coding RNA MALAT1 as a valuable biomarker for prognosis in osteosarcoma: A systematic review and meta-analysis” (Int J Surg 2019;72:206–213)

A commentary on “Long non-coding RNA MALAT1 as a valuable biomarker for prognosis in osteosarcoma: A systematic review and meta-analysis” (Int J Surg 2019;72:206–213)

Long non-coding RNA MALAT1 as a valuable biomarker for prognosis in osteosarcoma: A systematic review and meta-analysis.

Long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (lncRNA, MALAT1) has been found to be aberrantly expressed in osteosarcoma, while high MALAT1 expression is correlated with both metastasis and prognosis. This meta-analysis set out to investigate the prognostic value of lncRNA MALAT1 in patients living with osteosarcoma. We conducted a systematical search of available databases from inception to May 2019. Odds ratios (OR) of clinical parameters, as well as hazard ratio (HR) of overall survival (OS), were calculated in order to evaluate the relationship between MALAT1 expression and the prognosis of patients living with osteosarcoma. Nine eligible studies which included a total of 599 osteosarcoma patients were enrolled in the present study. Pooled results found that high MALAT1 expression was associated with clinical stage and distant metastasis, but not age, gender, tumor anatomical location or tumor size. When compared to patients with low MALAT1 expression, patients with high MALAT1 expression were markedly correlated with a worse OS. Moreover, MALAT1 may be an independent predictive factor for OS in patients living with osteosarcoma. This meta-analysis suggests that high MALAT1 expression is associated with advanced clinicopathological features as well as unfavorable prognosis. LncRNA MALAT1 has the potential to serve as a moderate prognostic biomarker for osteosarcoma.

MiR-193a regulates chemoresistance of human osteosarcoma cells via repression of IRS2

Chemoresistance prevents curative potential of chemotherapy in most cases. MicroRNAs (miRNAs) are key players in regulating chemoresistance in osteosarcoma, which is the most common primary bone cancer. Bisulfite sequencing and quantitative real time PCR analyses showed that miR-193a expression is downregulated by DNA hypermethylation at its promoter region in a chemoresistant cell line, SJSA-1, compared to a chemosensitive cell line G-292. Introduction of a miR-193a mimic in SJSA-1 cells or an antagomir into G-292 cells confirmed the role of miR-193a in osteosarcoma chemoresistance. Bioinformatics together with biochemical assays showed that insulin receptor substrate 2 (IRS2) is a target of miR-193a. Our data concludes that miR-193a plays a role in the osteosarcoma chemoresistance and thus might serve as a useful biomarker for osteosarcoma prognosis.

Circular RNA circ-NT5C2 acts as a potential novel biomarker for prognosis of osteosarcoma.

Recent evidence suggests that circular RNAs (circRNAs) play important roles in multiple diseases, including cancer. Circ-NT5C2 was reported to be up-regulated in osteosarcoma. However, the clinical significance of circ-NT5C2 remains largely unclear. The aim of the current study was to investigate the value of circ-NT5C2 for the prognosis of patients with osteosarcoma. the expression of circ-NT5C2 in osteosarcoma tissues and corresponding normal tissues were explored by quantitative real-time polymerase chain reaction (qRT-PCR) experiments. The association of circ-NT5C2 expression with clinicopathological factors or the prognosis of osteosarcoma patients was also analyzed. Kaplan-Meier survival analysis was performed to analyze the association of circ-NT5C2 expression with overall survival (OS) and disease-free survival (DFS) of patients. Univariate and multivariate Cox-regression analyses were used to identify risk factors for poor prognosis. Our data showed a significant increase of circ-NT5C2 expression in osteosarcoma tissues compared with adjacent normal bone tissues (p < 0.01). In addition, we found that the level of circ-NT5C2 in osteosarcoma was strongly correlated with clinical stage (p = 0.006) and distant metastasis (p = 0.001). Importantly, patients with high expression of circ-NT5C2 had a shorter OS (p = 0.006) and DFS (p = 0.001) than those with low expression of circ-NT5C2. Finally, Cox regression analyses showed that high circ-NT5C2 expression might be an independent prognostic parameter to predict poor prognosis. Our findings indicated that circ-NT5C2 is significantly up-regulated in osteosarcoma tissues. Circ-NT5C2 may represent a new marker of prognosis in osteosarcoma.

High CCL5 expression is associated with osteosarcoma metastasis and poor prognosis of patients with osteosarcoma.

Osteosarcoma is the most common primary malignant tumor of the skeletal system and is characterized by an aggressive clinical course and high metastatic potential. Regulated upon Activation Normal T cell Expressed and Secreted, also termed C‑C motif chemokine ligand 5 (CCL5), is associated with metastasis and poor prognosis in various types of cancer. The aim of the current study was to investigate the association between CCL5 expression and clinicopathological features and prognosis in patients with osteosarcoma. Tissue microarrays and reverse transcription‑quantitative polymerase chain reaction and immunohistochemistry were used to examine the expression of CCL5 in human osteosarcoma tissues. The prognostic value of CCL5 expression was evaluated by the Kaplan‑Meier method and Cox proportional hazards regression model. The rate of high CCL5 expression was significantly higher in metastatic osteosarcomas than in osteosarcomas without metastases. The overall survival rates (P=0.001) and the metastasis‑free survival rates (P<0.001) of the low CCL5 expression group were significantly higher than the CCL5 high expression group. Multivariate Cox regression analysis indicated that CCL5 expression had independent predictive value for the prognosis of patients with osteosarcoma. In conclusion, the data of the current study indicated that CCL5 may serve as a biomarker for prognosis of osteosarcoma, and may be a potential molecular target for osteosarcoma therapy.