scholarly journals ONZIN Upregulation by Mutant p53 Contributes to Osteosarcoma Metastasis Through the CXCL5-MAPK Signaling Pathway

2018 ◽  
Vol 48 (3) ◽  
pp. 1099-1111 ◽  
Author(s):  
Yanqin Zhang ◽  
Qianghua Hu ◽  
Guixin Li ◽  
Lili Li ◽  
Shoulei Liang ◽  
...  
Keyword(s):  
Lung Metastasis ◽  
Clonogenic Survival ◽  
Mapk Signaling ◽  
High Rate ◽  
Migration And Invasion ◽  
Mutant P53 ◽  
Osteosarcoma Cell ◽  
Expression Array ◽  
Human Osteosarcoma

Background/Aims: 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. Methods: 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. Results: 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. Conclusions: Overexpression of ONZIN promotes osteosarcoma progression and metastasis, and can serve as a clinical biomarker for osteosarcoma metastasis and prognosis.

scholarly journals MiR-125b Functions as a Tumor Suppressor and Enhances Chemosensitivity to Cisplatin in Osteosarcoma

2016 ◽  
Vol 15 (6) ◽  
pp. NP105-NP112 ◽  
Author(s):  
Fei Wang ◽  
Dapeng Yu ◽  
Zhen Liu ◽  
Ruijie Wang ◽  
Yan Xu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Noncoding Rna ◽  
Migration And Invasion ◽  
Osteosarcoma Cell ◽  
Human Osteosarcoma ◽  
Translational Level

MicroRNAs are highly conserved noncoding RNA that negatively modulate protein expression at a posttranscriptional and/or translational level and are deeply involved in the pathogenesis of several types of cancers. To date, the potential microRNAs regulating the growth and progression of osteosarcoma are not fully identified yet. Previous reports have shown differentially expressed miR-125b in osteosarcoma. However, the role of miR-125b in human osteosarcoma has not been totally illuminated. In this study, we have shown that miR-125b was downregulated in human osteosarcoma tissues compared to the adjacent tissues and effects as a tumor suppressor in vitro. We found that stable overexpression of miR-125b in osteosarcoma cell lines U2OS and MG-63 inhibited cell proliferation, migration, and invasion. Our data also verified that Bcl-2 is the target of miR-125b. Meanwhile, we showed that Bcl-2 was inversely correlated with miR-125b in osteosarcoma tissues. More importantly, we proved that miR-125b increased the chemosensitivity of osteosarcoma cell lines to cisplatin by targeting Bcl-2. In conclusion, our data demonstrate that miR-125b is a tumor suppressor and support its potential application for the treatment of osteosarcoma in the future.

11-O-Galloyl Bergenin from Corylopsis coreanas Leaves Induces Autophagy and Apoptosis in Human Osteosarcoma

2021 ◽  
Vol 49 (08) ◽  
pp. 2017-2031
Author(s):  
Kyung-Ran Park ◽  
Yoon-Ju Kwon ◽  
Myounglae Cho ◽  
Il Keun Kwon ◽  
Jin Tae Hong ◽  
...  
Keyword(s):  
Annexin V ◽  
Mg63 Cell ◽  
Underlying Mechanism ◽  
Mapk Signaling ◽  
Migration And Invasion ◽  
Boyden Chamber ◽  
Antitumor Effects ◽  
Human Osteosarcoma ◽  
Human Osteosarcoma Cells ◽  
Induced Apoptosis

Osteosarcoma is the most common malignant bone-forming tumor, wherein most patients with high grade osteosarcomas are treated with chemotherapy. Despite this, survival for metastatic or relapsed osteosarcoma patients has remained at an overall 5-year survival rate of 20%. In particular, the extracts of Corylopsis coreana (Korean winter hazel), a cultivated woody plant in South Korea, have shown beneficial anti-inflammatory, anti-oxidative, anti-osteoclastic, and antihyperuricemic properties. Therefore, this study aimed to demonstrate the antitumor activities and underlying mechanism of 11-O-Galloyl bergenin (OGAL) isolated from Corylopsis coreanas leaves in human osteosarcoma cells. Herein, we found that OGAL inhibited MG63 cell proliferation and induced cellular apoptosis as evidenced by cleaved-PARP, cleaved-caspase 3, TUNEL-positive cells, and Annexin V-positive cells. Specifically, OGAL-induced apoptosis was accompanied by p53 and p21 upregulation, BAX expression, and decreased Bcl-2 and cdk2. Moreover, OGAL induced autophagy via AKT inactivation, LC3II upregulation, and MG63 cell autophagosome formation. OGAL-induced autophagy was also accompanied by increased p38 phosphorylation, whereas JNK and ERK1/2 activities were found to be unaffected upon examining the MAPK signaling pathway. Furthermore, wound healing and Boyden chamber assays showed that OGAL suppressed MG63 cell migration and invasion. Given these findings, this study provided evidence that OGAL has antitumor effects by apoptosis and autophagy enhancement through increased p53, AKT, and p38 signaling, suggesting that OGAL may be a potential therapeutic strategy for osteosarcoma treatment.

LncRNA GAS5 suppresses the proliferation and invasion of osteosarcoma cells via the miR-23a-3p/PTEN/PI3K/AKT pathway

2020 ◽  
Author(s):  
Jianmin Liu ◽  
Ming Chen ◽  
Longyang Ma ◽  
Xingbo Dang ◽  
Gongliang Du
Keyword(s):  
Tumor Suppressor ◽  
Tumor Growth ◽  
Akt Pathway ◽  
Osteosarcoma Cell ◽  
Osteosarcoma Cells ◽  
Cell Behaviors ◽  
Human Osteosarcoma ◽  
Proliferation And Invasion

Abstract Background: Accumulating evidence has shown that lncRNA growth arrest special 5 (GAS5) is a well‑known tumor suppressor in the pathogenesis of a variety of human cancers. However, the detailed role of GAS5 in osteosarcoma is largely unclear. Here, we explore the role of GAS5 in progression of osteosarcoma. Methods: The expression level of GAS5 was detected in human osteosarcoma tissues and matched adjacent tissues, as well as osteosarcoma cell lines and non-malignant osteoblast cells. Then, in vitro gain- and loss-of-function experiments, with the pcDNA-GAS5 expression vector and GAS5-siRNA, were performed in U2OS and HOS cells to determine the effect of GAS5 on osteosarcoma cell proliferation and invasion. Subsequently, we searched potential miRNA targets with bioinformatics analysis and confirmed their interaction by using luciferase reporter gene and RNA pull-down assays. The function and mechanism of miR-23a-3p in proliferation and invasion was also investigated in U2OS and HOS cells. Furthermore, rescue experiments were performed to verify the involvement of miR-23a-3p and its target gene in GAS5-mediated cell behaviors. Finally, a xenograft nude mouse model was established by subcutaneous injection with U2OS cells overexpressing GAS5 or not, and the effect of GAS5 on tumor growth in vivo was evaluated. Results: GAS5 was downregulated in human osteosarcoma tissues and cell lines. Overexpression of GAS5 could significantly suppress, and downregulation of GAS5 promoted, proliferation and invasion of osteosarcoma cells. GAS5 could directly bind with and downregulated miR-23a-3p that post-transcriptionally downregulated the tumor suppressor PTEN and positively regulated proliferation and invasion of osteosarcoma cells. Rescue experiments confirmed the involvement of miR-23a-3p and PTEN in GAS5-mediated cell behaviors by modifying the phosphatidylinositol-3-kinases/protein-serine-threonine kinase (PI3K/AKT) pathway. GAS5 could inhibit tumor growth in vivo . Conclusion: GAS5 functions as a competing endogenous RNA , sponging miR-23a-3p, to promote PTEN expression and suppress cell growth and invasion in osteosarcoma by regulating the PI3K/AKT pathway.

scholarly journals Identification of Kinesin Family Member 2A (KIF2A) as a Promising Therapeutic Target for Osteosarcoma

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Zhe-Xiang Wang ◽  
Shao-Chun Ren ◽  
Zi-Song Chang ◽  
Jing Ren
Keyword(s):  
Tumor Growth ◽  
Cancer Progression ◽  
Therapeutic Target ◽  
Clinical Stage ◽  
Migration And Invasion ◽  
Osteosarcoma Cell ◽  
Expression Levels ◽  
Human Osteosarcoma ◽  
Promising Therapeutic Target ◽  
Tumor Growth And Metastasis

Background. Osteosarcoma is known as a type of common human bone malignancy, and more therapeutic targets are still required to combat this disease. In recent years, the involvement of KIF2A in cancer progression has been widely revealed; however, its potential effect on osteosarcoma development remains unknown. This study is to assess the KIF2A expression levels in human osteosarcoma tissues and explore its potential role in osteosarcoma development. Methods. Immunohistochemical (IHC) assays were conducted to evaluate the expression levels of KIF2A in a total of 74 samples of osteosarcoma tissues and adjacent nontumor tissues. According to the staining intensity in tumor tissues, patients were divided into highly expressed and low expression KIF2A groups. The possible links between the KIF2A expression and the clinical pathological features were explored and analyzed, and the effects of KIF2A on osteosarcoma cell proliferation, migration, and invasion were detected through colony formation assay, MTT assay, wound closure assay, and transwell assay, respectively. The effects of KIF2A on tumor growth and metastasis were detected by the use of animal models. Results. KIF2A was highly expressed in human osteosarcoma tissues. Meanwhile, KIF2A was obviously correlated to the tumor size ( P = 0.001 ∗ ) and clinical stage ( P = 0.014 ∗ ) of osteosarcoma patients. Our results also revealed that the ablation of KIF2A dramatically blocked the proliferation, migration, and invasion capacity of osteosarcoma cells in vitro and blocked tumor growth and metastasis in mice. Conclusions. We investigated the involvement of KIF2A in the development and metastasis of osteosarcoma and therefore thought KIF2A as a promising therapeutic target for osteosarcoma treatment.

scholarly journals Long noncoding RNA 00976 promotes pancreatic cancer progression through OTUD7B by sponging miR-137 involving EGFR/MAPK pathway

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Shan Lei ◽  
Zhiwei He ◽  
Tengxiang Chen ◽  
Xingjun Guo ◽  
Zhirui Zeng ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Migration And Invasion ◽  
Potential Biomarker

Abstract Background Accumulation evidence indicates the vital role of long non-coding RNAs (lncRNAs) in tumorigenesis and the progression of malignant tumors, including pancreatic cancer (PC). However, the role and the molecular mechanism of long non-coding RNA 00976 is unclear in pancreatic cancer. Methods In situ hybridization (ISH) and qRT-PCR was performed to investigate the association between linc00976 expression and the clinicopathological characteristics and prognosis of patients with PC. Subsequently, linc00976 over-expression vector and shRNAs were transfected into PC cells to up-regulate or down-regulate linc00976 expression. Loss- and gain-of function assays were performed to investigate the role of linc00976 in proliferation and metastasis in vitro and vivo. ITRAQ, bioinformatic analysis and rescue assay were used to illustrate the ceRNA mechanism network of linc00976/miR-137/OTUD7B and its downstream EGFR/MAPK signaling pathway. Results linc00976 expression was overexpressed in PC tissues and cell lines and was positively associated with poorer survival in patients with PC. Function studies revealed that linc00976 knockdown significantly suppressed cell proliferation, migration and invasion in vivo and in vitro, whereas its overexpression reversed these effects. Based on Itraq results and online database prediction, Ovarian tumor proteases OTUD7B was found as a downstream gene of linc00976, which deubiquitinated EGFR mediates MAPK signaling activation. Furthermore, Bioinformatics analysis and luciferase assays and rescue experiments revealed that linc00976/miR137/OTUD7B established the ceRNA network modulating PC cell proliferation and tumor growth. Conclusion The present study demonstrates that linc00976 enhances the proliferation and invasion ability of PC cells by upregulating OTUD7B expression, which was a target of miR-137. Ultimately, OTUD7B mediates EGFR and MAPK signaling pathway, suggesting that linc00976/miR-137/OTUD7B/EGFR axis may act as a potential biomarker and therapeutic target for PC.

scholarly journals Breast tumor cell-specific knockout of Twist1 inhibits cancer cell plasticity, dissemination, and lung metastasis in mice

2017 ◽  
Vol 114 (43) ◽  
pp. 11494-11499 ◽  
Author(s):  
Yixiang Xu ◽  
Dong-Kee Lee ◽  
Zhen Feng ◽  
Yan Xu ◽  
Wen Bu ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Lung Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Early Stage ◽  
Migration And Invasion ◽  
Small Subset ◽  
Cell Plasticity ◽  
Mesenchymal Transition

Twist1 is an epithelial–mesenchymal transition (EMT)-inducing transcription factor (TF) that promotes cell migration and invasion. To determine the intrinsic role of Twist1 in EMT and breast cancer initiation, growth, and metastasis, we developed mouse models with an oncogene-induced mammary tumor containing wild-type (WT) Twist1 or tumor cell-specific Twist1 knockout (Twist1TKO). Twist1 knockout showed no effects on tumor initiation and growth. In both models with early-stage tumor cells, Twist1, and mesenchymal markers were not expressed, and lung metastasis was absent. Twist1 expression was detected in ∼6% of the advanced WT tumor cells. Most of these Twist1+ cells coexpressed several other EMT-inducing TFs (Snail, Slug, Zeb2), lost ERα and luminal marker K8, acquired basal cell markers (K5, p63), and exhibited a partial EMT plasticity (E-cadherin+/vimentin+). In advanced Twist1TKO tumor cells, Twist1 knockout largely diminished the expression of the aforementioned EMT-inducing TFs and basal and mesenchymal markers, but maintained the expression of the luminal markers. Circulating tumor cells (CTCs) were commonly detected in mice with advanced WT tumors, but not in mice with advanced Twist1TKO tumors. Nearly all WT CTCs coexpressed Twist1 with other EMT-inducing TFs and both epithelial and mesenchymal markers. Mice with advanced WT tumors developed extensive lung metastasis consisting of luminal tumor cells with silenced Twist1 and mesenchymal marker expression. Mice with advanced Twist1TKO tumors developed very little lung metastasis. Therefore, Twist1 is required for the expression of other EMT-inducing TFs in a small subset of tumor cells. Together, they induce partial EMT, basal-like tumor progression, intravasation, and metastasis.

scholarly journals Inhibition of DEC2 is Necessary for Exiting Cell Dormancy in Salivary Adenoid Cystic Carcinoma 

2020 ◽  
Author(s):  
Xiao Yang ◽  
Jia-shun Wu ◽  
Mao Li ◽  
Wei-long Zhang ◽  
Xiao-lei Gao ◽  
...  
Keyword(s):  
Adenoid Cystic Carcinoma ◽  
Lung Metastasis ◽  
Tumor Dormancy ◽  
Migration And Invasion ◽  
Salivary Adenoid Cystic Carcinoma ◽  
Adenoid Cystic ◽  
Metastasis Model ◽  
Cell Dormancy

Abstract Background: Patients were prone to have poor prognosis once dormant tumor cells being reactivated. However, the molecular mechanism of tumor cell dormancy remains poorly understood. This study aimed to investigate the function of DEC2 in the dormancy of salivary adenoid cystic carcinoma (SACC) in vitro and vivo. Methods: The function of DEC2 in tumor dormancy of SACC was investigated in nude mice by establishing primary and lung metastasis model. Meanwhile, the interaction between hypoxia and SACC dormancy and the role of DEC2 were demonstrated through CoCl2 induced hypoxia–mimicking microenvironments. Furthermore, the expression of DEC2 was detected by immunohistochemical staining in primary SACC samples with and without recurrence. Results: In the primary SACC, DEC2 overexpression inhibited cell proliferation, increased cell population arrested in G0/G1 phase, and participated in dormancy regulation, which limited tumor growth. Intriguingly, in the model of lung metastasis, the level of DEC2 was reduced significantly and resulted in dormancy exit and growth resumption of SACC cells. Then, we found that DEC2 may associate with hyoxia in contributing to tumor dormancy, which might provide a possible cue to explain the different roles of DEC2 in primary and metastasis lesions. And overexpression of DEC2 induced dormancy and promoted migration and invasion through activating EMT program. Finally, DEC2 positive expression was shown to be significantly correlated with recurrence and dormancy of SACC patients. Conclusions: These findings provide a novel insight into the role of DEC2 gene in tumor dormancy and metastasis.

scholarly journals Elevated expression of serine/threonine phosphatase type 5 correlates with malignant proliferation in human osteosarcoma.

1970 ◽  
Vol 64 (1) ◽  
Author(s):  
Kun Han ◽  
Zhihua Gan ◽  
Shuchen Lin ◽  
Haiyan Hu ◽  
Zan Shen ◽  
...  
Keyword(s):  
Cell Lines ◽  
Functional Role ◽  
Osteosarcoma Cell ◽  
Osteosarcoma Cells ◽  
Facs Analysis ◽  
Human Osteosarcoma ◽  
Human Osteosarcoma Cell ◽  
Elevated Expression ◽  
Common Primary Malignant Bone

Osteosarcoma is the most common primary malignant bone tumor in adolescents and young adults. However, the involvement of serine/threonine phosphatase type 5 (PP5) in osteosarcoma remains unclear. The aim of this study was to evaluate the functional role of PP5 in osteosarcoma cells. Firstly, we found that PP5 is widely expressed in several human osteosarcoma cell lines. Then we used lentivirus-delivered siRNA to silence PP5 expression in Saos-2 and U2OS cell lines. Knockdown of endogenous PP5 expression by shRNA-expressing lentivirus significantly decreased the viability and proliferation of the osteosarcoma cells. Moreover, FACS analysis showed that knockdown of PP5 expression induced a significant arrest in the G0/G1 phase of the cell cycle, which was associated with the inhibition of cell proliferation. Therefore, knockdown of PP5 is likely to provide a novel alternative to targeted therapy of osteosarcoma and deserves further investigation.

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