AHA1 upregulates IDH1 and metabolic activity to promote growth and metastasis and predicts prognosis in osteosarcoma

AbstractOsteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. Although activator of HSP90 ATPase activity 1 (AHA1) is reported to be a potential oncogene, its role in osteosarcoma progression remains largely unclear. Since metabolism reprogramming is involved in tumorigenesis and cancer metastasis, the relationship between AHA1 and cancer metabolism is unknown. In this study, we found that AHA1 is significantly overexpressed in osteosarcoma and related to the prognosis of osteosarcoma patients. AHA1 promotes the growth and metastasis of osteosarcoma both in vitro and in vivo. Mechanistically, AHA1 upregulates the metabolic activity to meet cellular bioenergetic needs in osteosarcoma. Notably, we identified that isocitrate dehydrogenase 1 (IDH1) is a novel client protein of Hsp90-AHA1. Furthermore, the IDH1 protein level was positively correlated with AHA1 in osteosarcoma. And IDH1 overexpression could partially reverse the effect of AHA1 knockdown on cell growth and migration of osteosarcoma. Moreover, high IDH1 level was also associated with poor prognosis of osteosarcoma patients. This study demonstrates that AHA1 positively regulates IDH1 and metabolic activity to promote osteosarcoma growth and metastasis, which provides novel prognostic biomarkers and promising therapeutic targets for osteosarcoma patients.

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Knockout of Ajuba Attenuates the Growth and Migration of Hepatocellular Carcinoma Cells

Cytogenetic and Genome Research ◽

10.1159/000512264 ◽

2020 ◽

Vol 160 (11-12) ◽

pp. 650-658

Author(s):

Yichen Le ◽

Yi He ◽

Meirong Bai ◽

Ying Wang ◽

Jiaxue Wu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Growth ◽

Cancer Progression ◽

Normal Liver ◽

Cell Growth And Migration ◽

And Migration ◽

Hcc Cells

Ajuba has been found to be mutated or aberrantly regulated in several human cancers and plays important roles in cancer progression via different signaling pathways. However, little is known about the role of Ajuba in hepatocellular carcinoma (HCC). Here, we found an upregulation of Ajuba expression in HCC tissues compared with normal liver tissues, while a poor prognosis was observed in HCC patients with high Ajuba expression. Knockout of Ajuba in HCC cells inhibited cell growth in vitro and in vivo, suppressed cell migration, and enhanced the cell apoptosis under stress. Moreover, re-expression of Ajuba in Ajuba-deficient cells could restore the phenotype of Ajuba-deficient cells. In conclusion, these results indicate that Ajuba is upregulated in HCC and promotes cell growth and migration of HCC cells, suggesting that Ajuba could possibly be a new target for HCC diagnosis and treatment.

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SMYD3 promotes hepatocellular carcinoma progression by methylating S1PR1 promoters

Cell Death and Disease ◽

10.1038/s41419-021-04009-8 ◽

2021 ◽

Vol 12 (8) ◽

Author(s):

Heyun Zhang ◽

Zhangyu Zheng ◽

Rongqin Zhang ◽

Yongcong Yan ◽

Yaorong Peng ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathways ◽

Histone Methylation ◽

Cell Growth And Migration ◽

Histone 3 ◽

Sphingosine 1 Phosphate ◽

And Migration ◽

Proliferation And Migration

AbstractHepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. SET and MYND domain-containing protein 3 (SMYD3) has been shown to promote the progression of various types of human cancers, including liver cancer; however, the detailed molecular mechanism is still largely unknown. Here, we report that SMYD3 expression in HCC is an independent prognostic factor for survival and promotes the proliferation and migration of HCC cells. We observed that SMYD3 upregulated sphingosine-1-phosphate receptor 1 (S1PR1) promoter activity by methylating histone 3 (H3K4me3). S1PR1 was expressed at high levels in HCC samples, and high S1PR1 expression was associated with shorter survival. S1PR1 expression was also positively correlated with SMYD3 expression in HCC samples. We confirmed that SMYD3 promotes HCC cell growth and migration in vitro and in vivo by upregulating S1PR1 expression. Further investigations revealed that SMYD3 affects critical signaling pathways associated with the progression of HCC through S1PR1. These findings strongly suggest that SMYD3 has a crucial function in HCC progression that is partially mediated by histone methylation at the downstream gene S1PR1, which affects key signaling pathways associated with carcinogenesis and the progression of HCC.

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BSCI-12. Inhibition of melanoma brain metastasis by targeting miR-146a

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab071.011 ◽

2021 ◽

Vol 3 (Supplement_3) ◽

pp. iii3-iii3

Author(s):

Jiwei Wang ◽

Emma Rigg ◽

Taral R Lunavat ◽

Wenjing Zhou ◽

Zichao Feng ◽

...

Keyword(s):

Brain Metastasis ◽

Tumor Cells ◽

Cell Lines ◽

Western Blots ◽

Cell Growth And Migration ◽

Human Astrocytes ◽

And Migration ◽

The Brain

Abstract Background Melanoma has the highest propensity of any cancer to metastasize to the brain, with late-stage patients developing brain metastasis (MBM) in 40% of cases. Survival of patients with MBM is around 8 months with current therapies, illustrating the need for new treatments. MBM development is likely caused by molecular interactions between tumor cells and the brain, constituting the brain metastatic niche. miRNAs delivered by exosomes released by the primary tumor cells may play a role in niche establishment, yet the mechanisms are poorly understood. Here, the aim was to identify miRNAs released by exosomes from melanomas, which may be important in niche establishment and MBM progression. Materials and Methods miRNAs from exosomes collected from human astrocytes, melanocytes, and MBM cell lines were profiled to determine differential expression. Functional in vitro validation was performed by cell growth and migration assays, cytokine arrays, qPCR and Western blots. Functional in vivo studies were performed after miR knockdown in MBM cell lines. An in silico docking study was performed to determine drugs that potentially inhibit transcription of miR-146a to impede MBM development. Results miR-146a was the most upregulated miRNA in exosomes from MBM cells and was highly expressed in human and animal MBM samples. miR-146a mimics activated human astrocytes, shown by increased proliferation and migration, elevated expression of GFAP in vitro and in mouse brain tumor samples, and increased cytokine production. In animal studies, knockdown of miR-146a in MBM cells injected intracardially into mice reduced BM burden and increased animal survival. Based on the docking studies, deserpidine was found to be an effective inhibitor of MBM growth in vitro and in vivo. Conclusions MiR-146a may play an important role in MBM development, and deserpidine is a promising candidate for clinical use.

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GNG5 is a novel oncogene associated with cell migration, proliferation, and poor prognosis in glioma

10.21203/rs.3.rs-49192/v2 ◽

2021 ◽

Author(s):

Wang Zhang ◽

Zhendong Liu ◽

Binchao Liu ◽

Miaomiao Jiang ◽

Shi Yan ◽

...

Keyword(s):

Signaling Pathways ◽

Clinical Data ◽

Poor Prognosis ◽

Glioma Cells ◽

Diagnosis And Treatment ◽

And Migration ◽

The Relationship ◽

Proliferation And Migration

Abstract Background: Although many biomarkers have been reported for detecting glioma, the prognosis for the disease remains poor, and therefore, new biomarkers need to be identified. GNG5, which is part of the G-protein family, has been associated with different malignant tumors, though the role of GNG5 in glioma has not been studied. Therefore, we aimed to identify the relationship between GNG5 and glioma prognosis and identify a new biomarker for the diagnosis and treatment of gliomas.Methods: We used data on more than a thousand gliomas from multiple databases and clinical data to determine the expression of GNG5 in glioma. Based on clinical data and CGGA database, we identified the correlation between GNG5 and multiple molecular and clinical features and prognosis using various analytical methods. Co-expression analysis and GSEA were performed to detect GNG5-related genes in glioma and possible signaling pathways involved. ESTIMATE, ssGSEA, and TIMER were used to detect the relationship between GNG5 and the immune microenvironment. Functional experiments were performed to explore the function of GNG5 in glioma cells.Results: GNG5 is highly expressed in gliomas, and its expression level is positively correlated with pathological grade, histological type, age, and tumor recurrence and negatively correlated with isocitrate dehydrogenase mutation, 1p/19 co-deletion, and chemotherapy. Moreover, GNG5 as an independent risk factor was negatively correlated with the overall survival time. GSEA revealed the potential signaling pathways involved in GNG5 function in gliomas, including cell adhesion molecules signaling pathway. The ssGSEA, ESTIMATE, and TIMER based analysis indicated a correlation between GNG5 expression and various immune cells in glioma. In vivo and in vitro experiments showed that GNG5 could participate in glioma cell proliferation and migration.Conclusions: Based on the large data platform and the use of different databases to corroborate results obtained using various datasets, as well as in vitro and in vivo experiments, our study reveals for the first time that GNG5, as an oncogene, is overexpressed in gliomas and can inhibit the proliferation and migration of glioma cells and lead to poor prognosis of patients. Thus, GNG5 is a potential novel biomarker for the clinical diagnosis and treatment of gliomas.

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P16.08 Inhibition of melanoma brain metastasis by targeting miR-146a

Neuro-Oncology ◽

10.1093/neuonc/noab180.199 ◽

2021 ◽

Vol 23 (Supplement_2) ◽

pp. ii57-ii57

Author(s):

J Wang ◽

E K Rigg ◽

T R Lunavat ◽

W Zhou ◽

Z Feng ◽

...

Keyword(s):

Brain Metastasis ◽

Tumor Cells ◽

Cell Lines ◽

Western Blots ◽

Cell Growth And Migration ◽

Human Astrocytes ◽

And Migration ◽

The Brain

Abstract BACKGROUND Melanoma has the highest propensity of any cancer to metastasize to the brain, with late-stage patients developing brain metastasis (MBM) in 40% of cases. Survival of patients with MBM is around 8 months with current therapies, illustrating the need for new treatments. MBM development is likely caused by molecular interactions between tumor cells and the brain, constituting the brain metastatic niche. miRNAs delivered by exosomes released from the primary tumor cells may play a role in niche establishment, yet the mechanisms are poorly understood. Here, the aim was to identify miRNAs released by exosomes from melanomas, which may be important in niche establishment and MBM progression. MATERIAL AND METHODS miRNAs in exosomes collected from human astrocytes, melanocytes, and MBM cell lines were profiled to determine differential expression. Functional in vitro validation was performed by cell growth and migration assays, cytokine arrays, qPCR and Western blots. Functional in vivo studies were performed after miR knockdown in MBM cell lines. An in silico docking study was performed to determine drugs that potentially inhibit transcription of miR-146a to impede MBM development. RESULTS miR-146a was the most upregulated miRNA in exosomes from MBM cells and was highly expressed in human and animal MBM samples. miR-146a mimics activated human astrocytes, shown by increased proliferation and migration, elevated expression of GFAP in vitro and in mouse brain tumor samples, and increased cytokine production. In animal studies, knockdown of miR-146 in MBM cells injected intracardially into mice reduced BM burden and increased animal survival. Based on the docking studies, deserpidine was found to be an effective inhibitor of MBM growth in vitro and in vivo. CONCLUSION miR-146a may play an important role in MBM development, and deserpidine is a promising candidate for clinical use.

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Chondroitin polymerizing factor (CHPF) promotes development of malignant melanoma through regulation of CDK1

Cell Death and Disease ◽

10.1038/s41419-020-2526-9 ◽

2020 ◽

Vol 11 (7) ◽

Author(s):

Wei Sun ◽

Fang Zhao ◽

Yu Xu ◽

Kai Huang ◽

Xianling Guo ◽

...

Keyword(s):

Malignant Melanoma ◽

Pathway Analysis ◽

Normal Skin ◽

Over Expression ◽

Tumor Promotor ◽

And Migration ◽

First Time ◽

The Relationship

Abstract Chondroitin polymerizing factor (CHPF) is an important member of glycosyltransferases involved in the biosynthesis of chondroitin sulfate (CS). However, the relationship between CHPF and malignant melanoma (MM) is still unknown. In this study, it was demonstrated that CHPF was up-regulated in MM tissues compared with the adjacent normal skin tissues and its high expression was correlated with more advanced T stage. Further investigations indicated that the over-expression/knockdown of CHPF could promote/inhibit proliferation, colony formation and migration of MM cells, while inhibiting/promoting cell apoptosis. Moreover, knockdown of CHPF could also suppress tumorigenicity of MM cells in vivo. RNA-sequencing followed by Ingenuity pathway analysis (IPA) was performed for exploring downstream of CHPF and identified CDK1 as the potential target. Furthermore, our study revealed that knockdown of CDK1 could inhibit development of MM in vitro, and alleviate the CHPF over-expression induced promotion of MM. In conclusion, our study showed, as the first time, CHPF as a tumor promotor for MM, whose function was carried out probably through the regulation of CDK1.

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Dual Effects ofβ3Integrin Subunit Expression on Human Pancreatic Cancer Models

Analytical Cellular Pathology ◽

10.1155/2010/917013 ◽

2010 ◽

Vol 33 (5-6) ◽

pp. 191-205 ◽

Cited By ~ 1

Author(s):

S. Marchán ◽

S. Pérez-Torras ◽

A. Vidal ◽

J. Adan ◽

F. Mitjans ◽

...

Keyword(s):

Pancreatic Cancer ◽

Rho Gtpases ◽

Cell Attachment ◽

Human Pancreatic Cancer ◽

Cell Growth And Migration ◽

Subunit Expression ◽

And Migration

Background: Pancreatic cancer, the fifth leading cause of adult cancer death in Western countries, lacks early detection, and displays significant dissemination ability. Accumulating evidence shows that integrin-mediated cell attachment to the extracellular matrix induces phenotypes and signaling pathways that regulate tumor cell growth and migration.Methods: In view of these findings, we examined the role ofβ3in pancreatic cancer by generating two stableβ3-expressing pancreatic human cell lines and characterizing their behavior in vitro and in vivo.Results: Transduction ofβ3selectively augmented the functional membraneαvβ3integrin levels, as evident from the enhanced adhesion and migration abilities related to active Rho GTPases. No effects on in vitro anchorage-dependent growth, but higher anoikis were detected inβ3-overexpressing cells. Moreover, tumors expressingβ3displayed reduced growth. Interestingly, treatment of mice with anαv-blocking antibody inhibited the growth ofβ3-expressing tumors to a higher extent.Conclusion: Our results collectively support the hypothesis thatαvβ3integrin has dual actions depending on the cell environment, and provide additional evidence on the role of integrins in pancreatic cancer, which should eventually aid in improving prediction of the effects of therapies addressed to modulate integrin activities in these tumors.

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Expression of Cadherin-17 Promotes Metastasis in a Highly Bone Marrow Metastatic Murine Breast Cancer Model

BioMed Research International ◽

10.1155/2017/8494286 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 8

Author(s):

Tomoko Okada ◽

Atsushi Kurabayashi ◽

Nobuyoshi Akimitsu ◽

Mutsuo Furihata

Keyword(s):

Breast Cancer ◽

Bone Marrow ◽

Subcutaneous Injection ◽

Cancer Metastasis ◽

Breast Cancer Metastasis ◽

Gene And Protein Expression ◽

Mouse Breast Cancer ◽

And Migration

We previously established 4T1E/M3 highly bone marrow metastatic mouse breast cancer cells through in vivo selection of 4T1 cells. But while the incidence of bone marrow metastasis of 4T1E/M3 cells was high (~80%) when injected intravenously to mice, it was rather low (~20%) when injected subcutaneously. Therefore, using 4T1E/M3 cells, we carried out further in vitro and in vivo selection steps to establish FP10SC2 cells, which show a very high incidence of metastasis to lungs (100%) and spines (85%) after subcutaneous injection into mice. qRT-PCR and western bolt analysis revealed that cadherin-17 gene and protein expression were higher in FP10SC2 cells than in parental 4T1E/M3 cells. In addition, immunostaining revealed the presence of cadherin-17 at sites of bone marrow and lung metastasis after subcutaneous injection of FP10SC2 cells into mice. Suppressing cadherin-17 expression in FP10SC2 cells using RNAi dramatically decreased the cells’ anchorage-independent growth and migration in vitro and their metastasis to lung and bone marrow in vivo. These findings suggest that cadherin-17 plays a crucial role in mediating breast cancer metastasis to bone marrow.

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TMOD-04. INHIBITION OF MELANOMA BRAIN METASTASIS BY TARGETING miR146a

Neuro-Oncology ◽

10.1093/neuonc/noaa215.955 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii228-ii228

Author(s):

Jiwei Wang ◽

Taral Lunavat ◽

Wenjing Zhou ◽

Zichao Feng ◽

Tuyen Hoang ◽

...

Keyword(s):

Brain Metastasis ◽

Tumor Cells ◽

Cell Lines ◽

Cell Growth And Migration ◽

Mirna Profiling ◽

Human Astrocytes ◽

Bm Niche ◽

And Migration

Abstract INTRODUCTION It is well known that cancer patients with brain metastasis (BM) have a poor prognosis and current treatments are not effective. It has been shown that BM development is caused by molecular interactions between the tumor cells and the normal brain, constituting the so-called brain metastatic niche. In this respect, miRNAs delivered by exosomes released by the primary tumor cells seem to be an important factor in BM niche establishment yet the mechanisms behind this process is poorly understood. AIM The aim of this project was to determine miRNAs released by exosomes from melanomas that may be important in establishing the BM niche, and to validate these findings in vitro and in vivo. METHODS We performed a miRNA profiling on exosomes collected from 3 human melanoma BM cell lines and from human astrocytes and melanocytes, to determine the most important differently expressed miRNAs. Functional in vitro validation was performed by cell growth and migration assays, cytokine arrays, qPCR and Western blots. Functional in vivo studies were performed after miR-knockdown in BM cell lines, in an experimental animal/tumor model. RESULTS AND DISCUSSION The miRNA profiling showed that miR-146a was by far the most differentially upregulated miRNA in exosomes from melanoma BM cell lines, compared to exosomes from normal cells. Mir-146a mimics activated human astrocytes, shown by increased proliferation and migration, elevated expression of GFAP in vitro and in mouse brain tumor samples, and increased cytokine production. These effects were reversed by adding anti-miR-146a to the experiments. In animal studies, knockdown of miR-146 in melanoma BM cells injected intracardially into nod/scid mice resulted in a significant reduction in BM burden, compared to wild type cells, and increased animal survival. CONCLUSIONS Inhibition of miR-146a reduces activation of the BM niche, leading to inhibition of BM development.

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GNG5 is a novel oncogene associated with cell migration, proliferation, and poor prognosis in glioma

Cancer Cell International ◽

10.1186/s12935-021-01935-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Wang Zhang ◽

Zhendong Liu ◽

Binchao Liu ◽

Miaomiao Jiang ◽

Shi Yan ◽

...

Keyword(s):

Signaling Pathways ◽

Clinical Data ◽

Poor Prognosis ◽

Glioma Cells ◽

Diagnosis And Treatment ◽

And Migration ◽

The Relationship ◽

Proliferation And Migration

Abstract Background Although many biomarkers have been reported for detecting glioma, the prognosis for the disease remains poor, and therefore, new biomarkers need to be identified. GNG5, which is part of the G-protein family, has been associated with different malignant tumors, though the role of GNG5 in glioma has not been studied. Therefore, we aimed to identify the relationship between GNG5 and glioma prognosis and identify a new biomarker for the diagnosis and treatment of gliomas. Methods We used data on more than a thousand gliomas from multiple databases and clinical data to determine the expression of GNG5 in glioma. Based on clinical data and CGGA database, we identified the correlation between GNG5 and multiple molecular and clinical features and prognosis using various analytical methods. Co-expression analysis and GSEA were performed to detect GNG5-related genes in glioma and possible signaling pathways involved. ESTIMATE, ssGSEA, and TIMER were used to detect the relationship between GNG5 and the immune microenvironment. Functional experiments were performed to explore the function of GNG5 in glioma cells. Results GNG5 is highly expressed in gliomas, and its expression level is positively correlated with pathological grade, histological type, age, and tumor recurrence and negatively correlated with isocitrate dehydrogenase mutation, 1p/19 co-deletion, and chemotherapy. Moreover, GNG5 as an independent risk factor was negatively correlated with the overall survival time. GSEA revealed the potential signaling pathways involved in GNG5 function in gliomas, including cell adhesion molecules signaling pathway. The ssGSEA, ESTIMATE, and TIMER based analysis indicated a correlation between GNG5 expression and various immune cells in glioma. In vivo and in vitro experiments showed that GNG5 could participate in glioma cell proliferation and migration. Conclusions Based on the large data platform and the use of different databases to corroborate results obtained using various datasets, as well as in vitro and in vivo experiments, our study reveals for the first time that GNG5, as an oncogene, is overexpressed in gliomas and can inhibit the proliferation and migration of glioma cells and lead to poor prognosis of patients. Thus, GNG5 is a potential novel biomarker for the clinical diagnosis and treatment of gliomas.

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