scholarly journals LOXL1 confers antiapoptosis and promotes gliomagenesis through stabilizing BAG2

2020 ◽  
Vol 27 (11) ◽  
pp. 3021-3036 ◽  
Author(s):  
Hua Yu ◽  
Jun Ding ◽  
Hongwen Zhu ◽  
Yao Jing ◽  
Hu Zhou ◽  
...  
Keyword(s):  
Molecular Chaperone ◽  
Glioma Cell ◽  
Lysyl Oxidase ◽  
The Cancer Genome Atlas ◽  
Loss Of Function ◽  
Protein Levels ◽  
Important Mediator ◽  
Cancer Genome Atlas ◽  
Potential Strategy ◽  
Glioma Progression

Abstract The lysyl oxidase (LOX) family is closely related to the progression of glioma. To ensure the clinical significance of LOX family in glioma, The Cancer Genome Atlas (TCGA) database was mined and the analysis indicated that higher LOXL1 expression was correlated with more malignant glioma progression. The functions of LOXL1 in promoting glioma cell survival and inhibiting apoptosis were studied by gain- and loss-of-function experiments in cells and animals. LOXL1 was found to exhibit antiapoptotic activity by interacting with multiple antiapoptosis modulators, especially BAG family molecular chaperone regulator 2 (BAG2). LOXL1-D515 interacted with BAG2-K186 through a hydrogen bond, and its lysyl oxidase activity prevented BAG2 degradation by competing with K186 ubiquitylation. Then, we discovered that LOXL1 expression was specifically upregulated through the VEGFR-Src-CEBPA axis. Clinically, the patients with higher LOXL1 levels in their blood had much more abundant BAG2 protein levels in glioma tissues. Conclusively, LOXL1 functions as an important mediator that increases the antiapoptotic capacity of tumor cells, and approaches targeting LOXL1 represent a potential strategy for treating glioma. In addition, blood LOXL1 levels can be used as a biomarker to monitor glioma progression.

scholarly journals TRIM27 interacts with Iκbα to promote the growth of human renal cancer cells through regulating the NF-κB pathway

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chengwu Xiao ◽  
Wei Zhang ◽  
Meimian Hua ◽  
Huan Chen ◽  
Bin Yang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Prognostic Indicator ◽  
The Cancer Genome Atlas ◽  
Mrna Levels ◽  
Loss Of Function ◽  
Protein Levels ◽  
Kaplan Meier ◽  
Cancer Genome Atlas

Abstract Background The tripartite motif (TRIM) family proteins exhibit oncogenic roles in various cancers. The roles of TRIM27, a member of the TRIM super family, in renal cell carcinoma (RCC) remained unexplored. In the current study, we aimed to investigate the clinical impact and roles of TRIM27 in the development of RCC. Methods The mRNA levels of TRIM27 and Kaplan–Meier survival of RCC were analyzed from The Cancer Genome Atlas database. Real-time PCR and Western blotting were used to measure the mRNA and protein levels of TRIM27 both in vivo and in vitro. siRNA and TRIM27 were exogenously overexpressed in RCC cell lines to manipulate TRIM27 expression. Results We discovered that TRIM27 was elevated in RCC patients, and the expression of TRIM27 was closely correlated with poor prognosis. The loss of function and gain of function results illustrated that TRIM27 promotes cell proliferation and inhibits apoptosis in RCC cell lines. Furthermore, TRIM27 expression was positively associated with NF-κB expression in patients with RCC. Blocking the activity of NF-κB attenuated the TRIM27-mediated enhancement of proliferation and inhibition of apoptosis. TRIM27 directly interacted with Iκbα, an inhibitor of NF-κB, to promote its ubiquitination, and the inhibitory effects of TRIM27 on Iκbα led to NF-κB activation. Conclusions Our results suggest that TRIM27 exhibits an oncogenic role in RCC by regulating NF-κB signaling. TRIM27 serves as a specific prognostic indicator for RCC, and strategies targeting the suppression of TRIM27 function may shed light on future therapeutic approaches.

Upregulation of SGOL2 Predicts Poor Prognosis and Facilitates Hepatocellular Carcinoma Progression via Dysregulating the Cell Cycle by Directly Activating MAD2

2021 ◽  
Author(s):  
Qingqing Hu ◽  
Xiaochu Hu ◽  
Yalei Zhao ◽  
Lingjian Zhang ◽  
Ya Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
The Cancer Genome Atlas ◽  
Loss Of Function ◽  
Protein Levels ◽  
Cancer Genome Atlas ◽  
Centromeric Protein ◽  
Hcc Cells

Abstract Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Shugoshin-like protein 2 (SGOL2) is a centromeric protein that ensures the correct and orderly process of mitosis by protecting and maintaining centripetal adhesions during meiosis and mitosis. However, the role of SGOL2 in cancer is not well understood. Methods: The mRNA and protein levels of SGOL2 and survival analysis were conducted in The Cancer Genome Atlas (TCGA) and further validated in 2 independent cohorts. Differential genes correlated with SGOL2 and mitotic arrest deficient 2 like 1 (MAD2) were obtained using LinkedOmics. Subsequently, loss-of-function and rescue assays were carried out in vitro and in vivo to assess the functions of SGOL2 in hepatic tumorigenisis. Findings: We found that SGOL2 was significantly overexpressed in HCC and predicted unfavorable overall survival in HCC patients. Next, we identified 47 differentially expressed genes positively correlated with both SGOL2 and MAD2 to be mainly involved in the cell cycle. In addition, SGOL2 downregulation suppressed the migration, invasion, proliferation, stemness and EMT of HCC cells and inhibited tumorigenesis in vivo. Furthermore, SGOL2 promoted tumor proliferation by activating MAD2-induced cell cycle dysregulation, which could be reversed by the MAD2 inhibitor M2I-1. We also proved that SGOL2 activated MAD2 by directly binding with MAD2. Conclusions: The results of this study showed that SGOL2 acts as an oncogene in HCC cells by directly activating MAD2 and then dysregulating the cell cycle, thereby providing a potential target for HCC patients in the future.

scholarly journals TRIM27 interacts with Iκbα to promote the growth of human renal cancer cells through regulating the NF-κB pathway

2021 ◽  
Author(s):  
Chengwu Xiao ◽  
Wei Zhang ◽  
Meimian Hua ◽  
Huan Chen ◽  
Bin Yang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Prognostic Indicator ◽  
The Cancer Genome Atlas ◽  
Mrna Levels ◽  
Loss Of Function ◽  
Protein Levels ◽  
Kaplan Meier ◽  
Cancer Genome Atlas

Abstract Background: The tripartite motif (TRIM) family proteins exhibit oncogenic roles in various cancers. The roles of TRIM27, a member of the TRIM super family, in renal cell carcinoma (RCC) remained unexplored. In the current study, we aimed to investigate the clinical impact and roles of TRIM27 in the development of RCC. Methods: The mRNA levels of TRIM27 and Kaplan–Meier survival of RCC were analyzed from The Cancer Genome Atlas database. Real-time PCR and Western blotting were used to measure the mRNA and protein levels of TRIM27 both in vivo and in vitro. siRNA and TRIM27 were exogenously overexpressed in RCC cell lines to manipulate TRIM27 expression. Results: We discovered that TRIM27 was elevated in RCC patients, and the expression of TRIM27 was closely correlated with poor prognosis. The loss of function and gain of function results illustrated that TRIM27 promotes cell proliferation and inhibits apoptosis in RCC cell lines. Furthermore, TRIM27 expression was positively associated with NF-κB expression in patients with RCC. Blocking the activity of NF-κB attenuated the TRIM27-mediated enhancement of proliferation and inhibition of apoptosis. TRIM27 directly interacted with Iκbα, an inhibitor of NF-κB, to promote its ubiquitination, and the inhibitory effects of TRIM27 on Iκbα led to NF-κB activation.Conclusions: Our results suggest that TRIM27 exhibits an oncogenic role in RCC by regulating NF-κB signaling. TRIM27 serves as a specific prognostic indicator for RCC, and strategies targeting the suppression of TRIM27 function may shed light on future therapeutic approaches.

Effect and mechanism of YB-1 knockdown on glioma cell growth, migration, and apoptosis

2020 ◽  
Vol 52 (2) ◽  
pp. 168-179 ◽  
Author(s):  
Huilin Gong ◽  
Shan Gao ◽  
Chenghuan Yu ◽  
Meihe Li ◽  
Ping Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Glioma Cell ◽  
Cell Transformation ◽  
Malignant Cell ◽  
Protein Levels ◽  
Glioma Progression

Abstract Y-box binding protein 1 (YB-1) is manifested as its involvement in cell proliferation and differentiation and malignant cell transformation. Overexpression of YB-1 is associated with glioma progression and patient survival. The aim of this study is to investigate the influence of YB-1 knockdown on glioma cell progression and reveal the mechanisms of YB-1 knockdown on glioma cell growth, migration, and apoptosis. It was found that the knockdown of YB-1 decreased the mRNA and protein levels of YB-1 in U251 glioma cells. The knockdown of YB-1 significantly inhibited cell proliferation, colony formation, and migration in vitro and tumor growth in vivo. Proteome and phosphoproteome data revealed that YB-1 is involved in glioma progression through regulating the expression and phosphorylation of major proteins involved in cell cycle, adhesion, and apoptosis. The main regulated proteins included CCNB1, CCNDBP1, CDK2, CDK3, ADGRG1, CDH-2, MMP14, AIFM1, HO-1, and BAX. Furthermore, it was also found that YB-1 knockdown is associated with the hypo-phosphorylation of ErbB, mTOR, HIF-1, cGMP-PKG, and insulin signaling pathways, and proteoglycans in cancer. Our findings indicated that YB-1 plays a key role in glioma progression in multiple ways, including regulating the expression and phosphorylation of major proteins associated with cell cycle, adhesion, and apoptosis.

scholarly journals Overexpression of CLEC18B Associates With the Proliferation, Migration, and Prognosis of Glioblastoma

ASN NEURO ◽  
2018 ◽  
Vol 10 ◽  
pp. 175909141878194 ◽  
Author(s):  
Rui-Ming Guo ◽  
Cheng-Bin Zhao ◽  
Peng Li ◽  
Liang Zhang ◽  
Su-Hua Zang ◽  
...  
Keyword(s):  
Inverse Correlation ◽  
The Cancer Genome Atlas ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Lectin Domain ◽  
Kaplan Meier ◽  
Cancer Genome Atlas ◽  
Interfering Rna

C-type lectin domain family 18 member B (CLEC18B), encoding a superfamily of CLEC, has been found to be expressed in some of cancer cells, which possibly indicates it associated with cancer. However, the defined functional characterizations of CLEC18B in glioblastoma multiforme (GBM) progression still remain unclear. To this end, clinical relevance of CLEC18B expression with GBM patients’ prognosis was analyzed both in The Cancer Genome Atlas dataset of 174 tissues and 40 GBM tumor tissues collected from our hospital by using the Kaplan–Meier survival and the Cox proportional hazard model. The role of CLEC18B in GBM was determined by loss-of-function assay using small interfering RNA approach in vitro. Functional and signaling analyses were also performed to understand how CLEC18B facilitated the aggressiveness of GBM at molecular and cellular levels using Cell Counting Kit-8 assay, wound-healing, transwell, and Western blot analyses. Results from our analyses showed that CLEC18B was markedly elevated in both GBM tissues and cells, and exhibited strong inverse correlation with overall survival in GBM patients. Moreover, CLEC18B was identified as an independent predictor of patient survival. Functionally, knockdown of CLEC18B inhibited the growth, migration, and invasion of GBM cells. Mechanistic studies revealed that silencing of CLEC18B resulted in downregulation of Wnt/β-catenin signaling activity. Collectively, our findings provide clinical, molecular, and cellular evidence of CLEC18B as a promising prognostic biomarker and therapeutic target for GBM.

scholarly journals Downregulated SPINK4 is associated with poor survival in colorectal cancer

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Xiaojie Wang ◽  
Qian Yu ◽  
Waleed M. Ghareeb ◽  
Yiyi Zhang ◽  
Xingrong Lu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Expression Data ◽  
Poor Survival ◽  
Protein Levels ◽  
Normal Tissues ◽  
Human Protein Atlas ◽  
Cancer Genome Atlas ◽  
Independent Indicator

Abstract Background SPINK4 is known as a gastrointestinal peptide in the gastrointestinal tract and is abundantly expressed in human goblet cells. The clinical significance of SPINK4 in colorectal cancer (CRC) is largely unknown. Methods We retrieved the expression data of 1168 CRC patients from 3 Gene Expression Omnibus (GEO) datasets (GSE24551, GSE39582, GSE32323) and The Cancer Genome Atlas (TCGA) to compare the expression level of SPINK4 between CRC tissues and normal colorectal tissues and to evaluate its value in predicting the survival of CRC patients. At the protein level, these results were further confirmed by data mining in the Human Protein Atlas and by immunohistochemical staining of samples from 81 CRC cases in our own center. Results SPINK4 expression was downregulated in CRC compared with that in normal tissues, and decreased SPINK4 expression at both the mRNA and protein levels was associated with poor prognosis in CRC patients from all 3 GEO datasets, the TCGA database and our cohort. Additionally, lower SPINK4 expression was significantly related to higher TNM stage. Moreover, in multivariate regression, SPINK4 was confirmed as an independent indicator of poor survival in CRC patients in all databases and in our own cohort. Conclusions We concluded that reduced expression of SPINK4 relates to poor survival in CRC, functioning as a novel indicator.

scholarly journals miRNA-144-5p/ITGA3 Suppressed the Tumor-Promoting Behaviors of Thyroid Cancer Cells by Downregulating ITGA3

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Jizong Zhang ◽  
Yan Zhong ◽  
Yiming Sang ◽  
Guanghui Ren
Keyword(s):  
Thyroid Cancer ◽  
Expression Profiles ◽  
The Cancer Genome Atlas ◽  
Luciferase Assay ◽  
Cell Behaviors ◽  
Protein Levels ◽  
Related Cell ◽  
Cancer Genome Atlas ◽  
Thyroid Cancer Cells ◽  
Insight Into

Objective. To ascertain the mechanism of miRNA-144-5p and ITGA3 in thyroid cancer (TC). Methods. From The Cancer Genome Atlas (TCGA), RNA expression profiles were obtained for the expression analysis of miRNAs and mRNAs in TC. qRT-PCR and western blot were utilized to measure the expression of miRNA-144-5p and ITGA3 at RNA and protein levels, respectively. The association between miRNA-144-5p and ITGA3 was validated by the dual-luciferase assay. CCK-8, scratch healing, transwell, and flow cytometry assays were employed to evaluate tumor-related cell behaviors. Results. Low-expressed miRNA-144-5p and high-expressed ITGA3 were found in TC cells relative to normal cells. miRNA-144-5p expression was positively associated with suppressive effects on proliferative, invasive, and migratory ability of TC cells while negatively associated with cell apoptosis. miRNA-144-5p inhibited ITGA3 expression in TC, and its overexpression remarkably reversed the tumor-promoting effects of overexpressed ITGA3 on the biological functions of TC. Conclusion. It is verified in our study that cell growth of TC is inhibited by the miRNA-144-5p/ITGA3 axis, which represents an underlying target for TC. This research proposed a new insight into the strategy of TC treatment.

scholarly journals Comprehensive assessment of TP53 loss of function using multiple combinatorial mutagenesis libraries

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Vincent Carbonnier ◽  
Bernard Leroy ◽  
Shai Rosenberg ◽  
Thierry Soussi
Keyword(s):  
Functional Data ◽  
Large Scale ◽  
The Cancer Genome Atlas ◽  
Saturation Mutagenesis ◽  
Missense Mutations ◽  
Expression Data ◽  
Loss Of Function ◽  
Proteomic Data ◽  
Cancer Genome Atlas ◽  
Combinatorial Mutagenesis

AbstractThe diagnosis of somatic and germline TP53 mutations in human tumors or in individuals prone to various types of cancer has now reached the clinic. To increase the accuracy of the prediction of TP53 variant pathogenicity, we gathered functional data from three independent large-scale saturation mutagenesis screening studies with experimental data for more than 10,000 TP53 variants performed in different settings (yeast or mammalian) and with different readouts (transcription, growth arrest or apoptosis). Correlation analysis and multidimensional scaling showed excellent agreement between all these variables. Furthermore, we found that some missense mutations localized in TP53 exons led to impaired TP53 splicing as shown by an analysis of the TP53 expression data from the cancer genome atlas. With the increasing availability of genomic, transcriptomic and proteomic data, it is essential to employ both protein and RNA prediction to accurately define variant pathogenicity.

scholarly journals Expression of FGF8, FGF18, and FGFR4 in Gastroesophageal Adenocarcinomas

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1092 ◽  
Author(s):  
Jomrich ◽  
Hudec ◽  
Harpain ◽  
Winkler ◽  
Timelthaler ◽  
...  
Keyword(s):  
Survival Rates ◽  
Predictive Marker ◽  
The Cancer Genome Atlas ◽  
Cancer Therapies ◽  
Data Set ◽  
Protein Levels ◽  
Cox Proportional Hazard ◽  
Anti Cancer ◽  
Cancer Genome Atlas ◽  
Cox Proportional Hazard Regression

Even though distinctive advances in the field of esophageal cancer therapy have occurred over the last few years, patients’ survival rates remain poor. FGF8, FGF18, and FGFR4 have been identified as promising biomarkers in a number of cancers; however no data exist on expression of FGF8, FGF18, and FGFR4 in adenocarcinomas of the esophago-gastric junction (AEG). A preliminary analysis of the Cancer Genome Atlas (TCGA) database on FGF8, FGF18, and FGFR4 mRNA expression data of patients with AEG was performed. Furthermore, protein levels of FGF8, FGF18, and FGFR4 in diagnostic biopsies and post-operative specimens in neoadjuvantly treated and primarily resected patients using immunohistochemistry were investigated. A total of 242 patients was analyzed in this study: 87 patients were investigated in the TCGA data set analysis and 155 patients in the analysis of protein expression using immunohistochemistry. High protein levels of FGF8, FGF18, and FGFR4 were detected in 94 (60.7%), 49 (31.6%) and 84 (54.2%) patients, respectively. Multivariable Cox proportional hazard regression models revealed that high expression of FGF8 was an independent prognostic factor for diminished overall survival for all patients and for neoadjuvantly treated patients. By contrast, FGF18 overexpression was significantly associated with longer survival rates in neoadjuvantly treated patients. In addition, FGF8 protein level correlated with Mandard regression due to neoadjuvant therapy, indicating potential as a predictive marker. In summary, FGF8 and FGF18 are promising candidates for prognostic factors in adenocarcinomas of the esophago-gastric junction and new potential targets for new anti-cancer therapies.

Molecular characterization of TP53 mutations and copy number change in colorectal cancers.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15143-e15143
Author(s):  
Maliha Nusrat ◽  
Ganiraju C. Manyam ◽  
Jonathan M. Loree ◽  
Michael Lam ◽  
Michael J. Overman ◽  
...  
Keyword(s):  
The Cancer Genome Atlas ◽  
Gene Copy ◽  
Mrna Levels ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Chi Square ◽  
Tp53 Mutations ◽  
Protein Levels ◽  
Copy Numbers ◽  
Chi Square Test

e15143 Background: TP53 mutations (mut) are prevalent in colorectal cancer (CRC) patients (pts) and can result in oncogenic gain of function effect as well as loss of tumor suppressor function depending on the mut. Methods: The Cancer Genome Atlas (TCGA) data of 220 CRC pts with tumors sequenced and gene copy numbers (CN) annotated was obtained. Pts with CMS subtype data also available were included (n = 167). Chi square test was used to compare frequency of TP53 mut and CN change among CMS subtypes. TP53 mRNA and protein levels were compared by TP53 mut and CN change using independent sample t test. Results: 86 (51.5%) pts were TP53 mutant, with 35.3% missense and 16.2% loss of function (LOF) mut. LOF mut included 14 non-sense and 13 frameshift mut, and occurred mostly in codons 213 and 306. Missense mut mostly affected codons 175, 248 and 273 in 10, 9 and 8 pts respectively. TP53 mut were most frequent in CMS2 and CMS4 subtypes (62.7 and 62.5% respectively). TP53 mut in CMS2 were mostly missense and CMS 4 pts mostly had LOF mut. TP53 CN loss was seen in 74.7% CMS 2, 68.8% CMS 4, 43.5% CMS 3 and 6.9% CMS1 pts. 84.9% pts with TP53 mut had CN loss vs 28.4% of wild type pts (p < 0.001). Frequency of TP53 CN loss did not vary significantly by type of TP53 mut. Pts with TP53 missense mut had higher p53 mRNA and protein levels than those with LOF mut. Pts with TP53 CN loss had lower mRNA levels but no change in protein levels than those with normal CN. Conclusions: The higher TP53 mRNA and protein levels with missense mut suggest possible gain of function. Research on interactions of TP53 change with wnt, myc, and TGF beta pathway genes may reveal synthetic lethal treatment combinations. [Table: see text]

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