scholarly journals Role of Lamin A/C as Candidate Biomarker of Aggressiveness and Tumorigenicity in Glioblastoma Multiforme

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1343
Author(s):  
Giuliana Gatti ◽  
Laura Vilardo ◽  
Carla Musa ◽  
Chiara Di Pietro ◽  
Fabrizio Bonaventura ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Nuclear Lamina ◽  
The Cancer Genome Atlas ◽  
Research Network ◽  
Fibrillar Structure ◽  
Lamin A ◽  
Nucleus Shape ◽  
Cancer Genome Atlas

Nuclear lamina components have long been regarded as scaffolding proteins, forming a dense fibrillar structure necessary for the maintenance of the nucleus shape in all the animal kingdom. More recently, mutations, aberrant localisation and deregulation of these proteins have been linked to several diseases, including cancer. Using publicly available data we found that the increased expression levels of the nuclear protein Lamin A/C correlate with a reduced overall survival in The Cancer Genome Atlas Research Network (TCGA) patients affected by glioblastoma multiforme (GBM). We show that the expression of the LMNA gene is linked to the enrichment of cancer-related pathways, particularly pathways related to cell adhesion and cell migration. Mimicking the modulation of LMNA in a GBM preclinical cancer model, we confirmed both in vitro and in vivo that the increased expression of LMNA is associated with an increased aggressiveness and tumorigenicity. In addition, delving into the possible mechanism behind LMNA-induced GBM aggressiveness and tumorigenicity, we found that the mTORC2 component, Rictor, plays a central role in mediating these effects.

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.

scholarly journals Reduced Lamin A/C does Not Facilitate Cancer Cell Transendothelial Migration but Compromises Lung Metastasis

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2383
Author(s):  
Francesco Roncato ◽  
Ofer Regev ◽  
Sara W. Feigelson ◽  
Sandeep Kumar Yadav ◽  
Lukasz Kaczmarczyk ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Lung Metastasis ◽  
Metastatic Cancer ◽  
Nuclear Lamina ◽  
Transendothelial Migration ◽  
Soft Agar ◽  
Lamin A ◽  
And Migration

The mechanisms by which the nuclear lamina of tumor cells influences tumor growth and migration are highly disputed. Lamin A and its variant lamin C are key lamina proteins that control nucleus stiffness and chromatin conformation. Downregulation of lamin A/C in two prototypic metastatic lines, B16F10 melanoma and E0771 breast carcinoma, facilitated cell squeezing through rigid pores, and reduced heterochromatin content. Surprisingly, both lamin A/C knockdown cells grew poorly in 3D spheroids within soft agar, and lamin A/C deficient cells derived from spheroids transcribed lower levels of the growth regulator Yap1. Unexpectedly, the transendothelial migration of both cancer cells in vitro and in vivo, through lung capillaries, was not elevated by lamin A/C knockdown and their metastasis in lungs was even dramatically reduced. Our results are the first indication that reduced lamin A/C content in distinct types of highly metastatic cancer cells does not elevate their transendothelial migration (TEM) capacity and diapedesis through lung vessels but can compromise lung metastasis at a post extravasation level.

scholarly journals HNRNPH1-stabilized LINC00662 promotes ovarian cancer progression by activating the GRP78/p38 pathway

Oncogene ◽  
2021 ◽  
Author(s):  
Yong Wu ◽  
Qinhao Guo ◽  
Xingzhu Ju ◽  
Zhixiang Hu ◽  
Lingfang Xia ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Progression ◽  
Prognostic Indicator ◽  
Mapk Signaling ◽  
The Cancer Genome Atlas ◽  
Cancer Genome Atlas ◽  
Proliferation And Metastasis ◽  
Nuclear Ribonucleoprotein

AbstractNumerous studies suggest an important role for copy number alterations (CNAs) in cancer progression. However, CNAs of long intergenic noncoding RNAs (lincRNAs) in ovarian cancer (OC) and their potential functions have not been fully investigated. Here, based on analysis of The Cancer Genome Atlas (TCGA) database, we identified in this study an oncogenic lincRNA termed LINC00662 that exhibited a significant correlation between its CNA and its increased expression. LINC00662 overexpression is highly associated with malignant features in OC patients and is a prognostic indicator. LINC00662 significantly promotes OC cell proliferation and metastasis in vitro and in vivo. Mechanistically, LINC00662 is stabilized by heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1). Moreover, LINC00662 exerts oncogenic effects by interacting with glucose-regulated protein 78 (GRP78) and preventing its ubiquitination in OC cells, leading to activation of the oncogenic p38 MAPK signaling pathway. Taken together, our results define an oncogenic role for LINC00662 in OC progression mediated via GRP78/p38 signaling, with potential implications regarding therapeutic targets for OC.

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.

LncRNA DCST1-AS1 functions as a competing endogenous RNA to regulate FAIM2 expression by sponging miR-1254 in hepatocellular carcinoma

2019 ◽  
Vol 133 (2) ◽  
pp. 367-379 ◽  
Author(s):  
Jing Chen ◽  
Di Wu ◽  
Yue Zhang ◽  
Yong Yang ◽  
Yunfei Duan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Significance ◽  
Biological Function ◽  
The Cancer Genome Atlas ◽  
Cycle Arrest ◽  
Cancer Genome Atlas ◽  
Apoptosis Inhibitor ◽  
Hcc Cells

Abstract Long non-coding RNAs (lncRNAs) play important roles in a variety of tumours; however, their biological function and clinical significance in hepatocellular carcinoma (HCC) are still unclear. In the present study, the clinical significance, biological function and regulatory mechanisms of lncRNA DCST1-AS1 in HCC were investigated. Differential lncRNAs in HCC were identified based on The Cancer Genome Atlas (TCGA) database. The biological function and mechanism of DCST1-AS1 were studied in vitro and in vivo. LncRNA DCST1-AS1 was highly expressed in HCC tissues, and the high expression of DCST1-AS1 was significantly correlated with larger tumours and shorter survival time. Moreover, DCST1-AS1 knockout significantly inhibited proliferation, promoted apoptosis and cycle arrest of HCC cells, and inhibited tumour growth in vivo. According to functional analysis, DCST1-AS1 competitively bound miR-1254, thus blocking the silencing effect of miR-1254 on the target gene Fas apoptosis inhibitor 2 (FAIM2). A novel lncRNA DCST1-AS1 that functions as an oncogene in HCC was discovered. DCST1-AS1 up-regulates the expression of FAIM2 by up-regulating the expression of miR-1254, ultimately promoting the proliferation of HCC cells. This research provides new therapeutic targets for HCC.

FBXW7γ is a tumor-suppressive and prognosis-related FBXW7 transcript isoform in ovarian serous cystadenocarcinoma

2020 ◽  
Vol 16 (25) ◽  
pp. 1921-1930
Author(s):  
Zhou Xu ◽  
Lin Zhuang ◽  
Xiaoyin Wang ◽  
Qianrong Li ◽  
Yan Sang ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Tissue Expression ◽  
The Cancer Genome Atlas ◽  
In Vivo Studies ◽  
Protein Coding ◽  
Serous Cystadenocarcinoma ◽  
Skov3 Cells ◽  
Cancer Genome Atlas

Aim: To explore FBXW7 protein-coding transcript isoform (α, β and γ) expression, their functions and prognostic value in ovarian serous cystadenocarcinoma (OSC). Materials & methods: FBXW7 transcript data were collected from The Cancer Genome Atlas and the Genotype-Tissue Expression project. IOSE, A2780 and SKOV3 cells were used for in vitro and in vivo studies. Results: FBXW7α and FBXW7γ are dominant protein-coding transcripts that were downregulated in OSC. FBXW7γ overexpression reduced the protein expression of c-Myc, Notch1 and Yap1 and suppressed OSC cell growth in vitro and in vivo. FBXW7γ expression was an independent indicator of longer disease-specific survival (HR: 0.588; 95% CI: 0.449–0.770) and progression-free survival (HR: 0.708; 95% CI: 0.562–0.892). Conclusion: FBXW7γ is a tumor-suppressive and might be the only prognosis-related FBXW7 transcript in OSC.

scholarly journals Local Delivery of Minocycline and Vorinostat Act Synergistically to Inhibit Recurrence of Gliomas

2020 ◽  
Author(s):  
Gang Zhao ◽  
Jun Jia ◽  
Lansheng Wang ◽  
Yongkang Zhang ◽  
Han Yang ◽  
...  
Keyword(s):  
High Performance ◽  
Postoperative Recurrence ◽  
The Cancer Genome Atlas ◽  
The Public ◽  
Continuous Release ◽  
Clinical Consequences ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Abstract Background:Postoperative recurrence is the main reason of poor clinical consequences in glioma patients, so preventing recurrence of tumors is crucial in management of gliomas. Methods:In this study, the expression of matrix metalloproteinases (MMPs)in tissues from normal were detected by using RNA-seq analysis.Glioma cases from the public databases (The Cancer Genome Atlas (TCGA), The Chinese Glioma Genome Atlas(CGGA), Betastasis) were included in this study.The hydrogelcontains minocycline (Mino) and vorinostat (Vor)(G/Mino + Vor) was formed under 365 nm when photoinitiator was added in. High Performance Liquid Chromatography (HPLC) assay was used to assessed the release of drugs in G/Mino + Vor hydrogel. MTT assay was used to explore the biosecurity of GelMA. Immunohistochemistry assay, ELISA assay, Tunel assay were used to demonstrate the antitumor effect of G/Mino + Vor hydrogel.Results:We developed G/Mino + Vor hydrogel successfully. Thenthe experiment in vitro and in vivo confirmed MMPs-responsive delivery of minocycline and vorinostat in hydrogel and the anti-glioma effect on incomplete tumor operation model, which indicated that G/Mino + Vor hydrogel effectively inhibited the recurrence of glioma after surgery.Conclusions: In summary, G/Mino + Vor hydrogel could continuous release minocycline and vorinostat in surgical cavity for inhibiting local recurrence of glioma after operation.

RBIO-04. LACTATE DEHYDROGENASE A (LDHA) MEDIATES NOVEL CROSSTALK BETWEEN METABOLIC GLYCOLYSIS AND CHROMATIN REMODELING

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi192-vi192
Author(s):  
Jie Li ◽  
Jianfang Ning ◽  
Tomoyuki Koga ◽  
Ming Li ◽  
Shan Zhu ◽  
...  
Keyword(s):  
Dna Repair ◽  
Lactate Dehydrogenase ◽  
The Cancer Genome Atlas ◽  
Site Directed Mutagenesis ◽  
Metabolic Function ◽  
Therapeutic Development ◽  
Cancer Genome Atlas ◽  
Radiation Induced

Abstract INTRODUCTION Lactate dehydrogenase A (LDHA) encodes an enzyme that catalyzes the inter-conversion between pyruvate and lactate in glycolysis. Here, we demonstrate that LDHA mediates a novel role in DNA repair independent of this metabolic function. METHODS siRNA screen, The Cancer Genome Atlas (TCGA) survival analysis, ionizing radiation (IR), g-H2AX, and chromatin assays, site-directed mutagenesis. RESULTS In an orthogonal siRNA-informatic screen to identify genes 1) when silenced caused IR sensitivity in patient-derived glioblastoma lines and 2) lowered expression is associated with improved survival in TCGA, LDHA surfaced as the top candidate. The survival association was validated by LDHA immunohistochemical staining in an independent collection of glioblastoma samples. In vitro and in vivo, silencing of LDHA sensitized glioblastoma lines to IR and enhanced radiation-induced g-H2AX accumulation. Such sensitization was not observed after treatment with an LDHA inhibitor, suggesting the metabolic function of LDHA is distinct from its role in DNA repair. Supporting this hypothesis, truncation mutations that suppressed the LDHA glycolysis function minimally affected its role in DNA repair. Mechanistically, cytoplasmic LDHA translocates into the nucleus in response to IR. This translocation was associated with subsequent chromatin transition into an open conformation and enhanced homologous recombination. CONCLUSION The novel LDHA function in DNA repair suggests intricate crosstalks between glycolytic metabolism and DNA repair, offering a new platform for glioblastoma therapeutic development.

scholarly journals The human intermediate prolactin receptor is a mammary proto-oncogene

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jacqueline M. Grible ◽  
Patricija Zot ◽  
Amy L. Olex ◽  
Shannon E. Hedrick ◽  
J. Chuck Harrell ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prolactin Receptor ◽  
The Cancer Genome Atlas ◽  
Cancer Tissue ◽  
Mcf7 Cells ◽  
Cancer Pathogenesis ◽  
Cancer Genome Atlas ◽  
Alternatively Spliced

AbstractThe hormone prolactin (PRL) and its receptor (hPRLr) are significantly involved in breast cancer pathogenesis. The intermediate hPRLr (hPRLrI) is an alternatively-spliced isoform, capable of stimulating cellular viability and proliferation. An analogous truncated mouse PRLr (mPRLr) was recently found to be oncogenic when co-expressed with wild-type mPRLr. The goal of this study was to determine if a similar transforming event occurs with the hPRLr in human breast epithelial cells and to better understand the mechanism behind such transformation. hPRLrL+I co-expression in MCF10AT cells resulted in robust in vivo and in vitro transformation, while hPRLrI knock-down in MCF7 cells significantly decreased in vitro malignant potential. hPRLrL+I heterodimers displayed greater stability than hPRLrL homodimers, and while being capable of activating Jak2, Ras, and MAPK, they were unable to induce Stat5a tyrosine phosphorylation. Both immunohistochemical breast cancer tissue microarray data and RNA sequencing analyses using The Cancer Genome Atlas (TCGA) identified that higher hPRLrI expression associates with triple-negative breast cancer. These studies indicate the hPRLrI, when expressed alongside hPRLrL, participates in mammary transformation, and represents a novel oncogenic mechanism.

scholarly journals The YAP1–NMU Axis Is Associated with Pancreatic Cancer Progression and Poor Outcome: Identification of a Novel Diagnostic Biomarker and Therapeutic Target

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1477 ◽  
Author(s):  
Yoo ◽  
Lee ◽  
Jun ◽  
Noh ◽  
Lee ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Progression ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
The Cancer Genome Atlas ◽  
Mesenchymal Transition ◽  
Tumor Group ◽  
Cancer Genome Atlas

Yes-associated protein (YAP)-1 is highly upregulated in pancreatic cancer and associated with tumor progression. However, little is known about the role of YAP1 and related genes in pancreatic cancer. Here, we identified target genes regulated by YAP1 and explored their role in pancreatic cancer progression and the related clinical implications. Analysis of different pancreatic cancer databases showed that Neuromedin U (NMU) expression was positively correlated with YAP1 expression in the tumor group. The Cancer Genome Atlas data indicated that high YAP1 and NMU expression levels were associated with poor mean and overall survival. YAP1 overexpression induced NMU expression and transcription and promoted cell motility in vitro and tumor metastasis in vivo via upregulation of epithelial–mesenchymal transition (EMT), whereas specific inhibition of NMU in cells stably expressing YAP1 had the opposite effect in vitro and in vivo. To define this functional association, we identified a transcriptional enhanced associate domain (TEAD) binding site in the NMU promoter and demonstrated that YAP1–TEAD binding upstream of the NMU gene regulated its transcription. These results indicate that the identified positive correlation between YAP1 and NMU is a potential novel drug target and biomarker in metastatic pancreatic cancer.

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