scholarly journals Genomic Instability-Related LncRNA Signature Predicts the Prognosis and Highlights LINC01614 Is a Tumor Microenvironment-Related Oncogenic lncRNA of Papillary Thyroid Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Xubin Dong ◽  
Cong Jin ◽  
Danxiang Chen ◽  
Yizuo Chen ◽  
Zhi-qiang Ye ◽  
...  

BackgroundGenomic instability (GI) is among the top ten characteristics of malignancy. Long non-coding RNAs (lncRNAs) are promising cancer biomarkers that are reportedly involved in GI. So far, the clinical value of GI-related lncRNAs (GIlncs) in papillary thyroid cancer (PTC) has not been clarified.MethodsIntegrative analysis of lncRNA expression and somatic mutation profiles was performed to identify GIlncs. Analysis of differentially expressed lncRNAs in the group with high- and low- cumulative number of somatic mutations revealed significant GIlncs in PTC. Univariate and multivariate Cox proportional hazard regression analyses were performed to identify hub-GIlncs.ResultsA computational model based on four lncRNAs (FOXD2-AS1, LINC01614, AC073257.2, and AC005082.1) was identified as a quantitative index using an in-silicon discovery cohort. GILS score was significantly associated with poor prognosis, as validated in the TCGA dataset and further tested in our local RNA-Seq cohort. Moreover, a combination of clinical characteristics and the composite GILS-clinical prognostic nomogram demonstrates satisfactory discrimination and calibration. Furthermore, the GILS score and FOXD2-AS1, LINC01614, AC073257.2, and AC005082.1 were also associated with driver mutations and multiple clinical-pathological variables, respectively. Moreover, RNA-Seq confirmed the expression patterns of FOXD2-AS1, LINC01614, AC073257.2, and AC005082.1 in PTC and normal thyroid tissues. Biological experiments demonstrated that downregulated or overexpressed LINC01614 affect PTC cell proliferation, migration, and invasion in vitro. Activation of the stromal and immune cell infiltration was also observed in the high LINC01614 group in the PTC microenvironment.ConclusionIn summary, we identified a signature for clinical outcome prediction in PTC comprising four lncRNAs associated with GI. A better understanding of the GI providing an alternative evaluation of the progression risk of PTC. Our study also demonstrated LINC01614 as a novel oncogenic lncRNA and verified its phenotype in PTC.

2021 ◽  
Author(s):  
Peng Hou ◽  
Quan Wan ◽  
Qing Wang ◽  
Xuechao Wu ◽  
Xiaojie Lu

Abstract Background: RAB34 is aberrantly expressed in various cancers and exhibits oncogenic properties. However, its function in glioma remains largely unclear. Herein, we investigated the clinical value and biological functions of RAB34 in glioma.Methods: In this study, we collected 697 RNA-seq data from The Cancer Genome Atlas (TCGA) dataset and 325 RNA-seq data from Chinese Glioma Genome Atlas (CGGA) dataset. CCK-8 and EdU assays were employed to assess cell proliferation ability. The transwell assay was utilized to explore cell migration and invasion capacities. Western blot coupled with qRT-PCR were employed to determine the protein, as well as RNA contents. The statistical analyses along with the graphical work were mainly implemented in the R software.Results: RAB34 expression was positively related to the glioma tumor grade, and predicted poor outcomes for glioma patients. RAB34 expression was significantly upregulated in classical and mesenchymal subtypes, and IDH wild-type gliomas. Additionally, RAB34 expression was regulated by promoter DNA methylation. Moreover, RAB34 expression was remarkably correlated with inflammatory activities, immune infiltration, and immune checkpoints in glioma. In vitro experiments demonstrated that inhibition of RAB34 restrained the growth, migration, as well as invasion of glioma cells, and reversed the epithelial-to-mesenchymal transition (EMT) process. Conclusion: Our findings established RAB34 as a novel progression-related biomarker and a possible immunotherapy target for glioma.


2021 ◽  
Author(s):  
Peng Hou ◽  
Quan Wan ◽  
Qing Wang ◽  
Xuechao Wu ◽  
Xiaojie Lu

Abstract Background RAB34 is aberrantly expressed in various cancers and exhibits oncogenic properties. However, its function in glioma remains largely unclear. Herein, we investigated the clinical value and biological functions of RAB34 in glioma. Methods In this study, we collected 697 RNA-seq data from The Cancer Genome Atlas (TCGA) dataset and 325 RNA-seq data from Chinese Glioma Genome Atlas (CGGA) dataset. CCK-8 and EdU assays were employed to assess cell proliferation ability. The transwell assay was utilized to explore cell migration and invasion capacities. Western blot coupled with qRT-PCR were employed to determine the protein, as well as RNA contents. The statistical analyses along with the graphical work were mainly implemented in the R software. Results RAB34 expression was positively related to the glioma tumor grade, and predicted poor outcomes for glioma patients. RAB34 expression was significantly upregulated in classical and mesenchymal subtypes, and IDH wild-type gliomas. Additionally, RAB34 expression was regulated by promoter DNA methylation. Moreover, RAB34 expression was remarkably correlated with inflammatory activities, immune infiltration, and immune checkpoints in glioma. In vitro experiments demonstrated that inhibition of RAB34 restrained the growth, migration, as well as invasion of glioma cells, and reversed the epithelial-to-mesenchymal transition (EMT) process. Conclusion Our findings established RAB34 as a novel progression-related biomarker and a possible immunotherapy target for glioma.


Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1020
Author(s):  
Stefan Grote ◽  
Guillermo Ureña-Bailén ◽  
Kenneth Chun-Ho Chan ◽  
Caroline Baden ◽  
Markus Mezger ◽  
...  

Background: Melanoma is the most lethal of all skin-related cancers with incidences continuously rising. Novel therapeutic approaches are urgently needed, especially for the treatment of metastasizing or therapy-resistant melanoma. CAR-modified immune cells have shown excellent results in treating hematological malignancies and might represent a new treatment strategy for refractory melanoma. However, solid tumors pose some obstacles for cellular immunotherapy, including the identification of tumor-specific target antigens, insufficient homing and infiltration of immune cells as well as immune cell dysfunction in the immunosuppressive tumor microenvironment (TME). Methods: In order to investigate whether CAR NK cell-based immunotherapy can overcome the obstacles posed by the TME in melanoma, we generated CAR NK-92 cells targeting CD276 (B7-H3) which is abundantly expressed in solid tumors, including melanoma, and tested their effectivity in vitro in the presence of low pH, hypoxia and other known factors of the TME influencing anti-tumor responses. Moreover, the CRISPR/Cas9-induced disruption of the inhibitory receptor NKG2A was assessed for its potential enhancement of NK-92-mediated anti-tumor activity. Results: CD276-CAR NK-92 cells induced specific cytolysis of melanoma cell lines while being able to overcome a variety of the immunosuppressive effects normally exerted by the TME. NKG2A knock-out did not further improve CAR NK-92 cell-mediated cytotoxicity. Conclusions: The strong cytotoxic effect of a CD276-specific CAR in combination with an “off-the-shelf” NK-92 cell line not being impaired by some of the most prominent negative factors of the TME make CD276-CAR NK-92 cells a promising cellular product for the treatment of melanoma and beyond.


2018 ◽  
Author(s):  
Avi Z. Rosenberg ◽  
Carrie Wright ◽  
Karen Fox-Talbot ◽  
Anandita Rajpurohit ◽  
Courtney Williams ◽  
...  

AbstractAccurate, RNA-seq based, microRNA (miRNA) expression estimates from primary cells have recently been described. However, this in vitro data is mainly obtained from cell culture, which is known to alter cell maturity/differentiation status, significantly changing miRNA levels. What is needed is a robust method to obtain in vivo miRNA expression values directly from cells. We introduce expression microdissection miRNA small RNA sequencing (xMD-miRNA-seq), a method to isolate cells directly from formalin fixed paraffin-embedded (FFPE) tissues. xMD-miRNA-seq is a low-cost, high-throughput, immunohistochemistry-based method to capture any cell type of interest. As a proof-of-concept, we isolated colon epithelial cells from two specimens and performed low-input small RNA-seq. We generated up to 600,000 miRNA reads from the samples. Isolated epithelial cells, had abundant epithelial-enriched miRNA expression (miR-192; miR-194; miR-200b; miR-200c; miR-215; miR-375) and overall similar miRNA expression patterns to other epithelial cell populations (colonic enteroids and flow-isolated colon epithelium). xMD-derived epithelial cells were generally not contaminated by other adjacent cells of the colon as noted by t-SNE analysis. xMD-miRNA-seq allows for simple, economical, and efficient identification of cell-specific miRNA expression estimates. Further development will enhance rapid identification of cell-specific miRNA expression estimates in health and disease for nearly any cell type using archival FFPE material.


2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Yuan-ming Jiang ◽  
Wei Liu ◽  
Ling Jiang ◽  
Hongbin Chang

Background. Circular RNAs (circRNAs) have been reported to play important roles in the development and progression of papillary thyroid carcinoma (PTC). However, the function and molecular mechanism of circRNA low-density lipoprotein receptor (circLDLR) in the tumorigenesis of PTC remain unknown. Results. In this study, circLDLR was found to be markedly upregulated in PTC tissues and cell lines, and knockdown of circLDLR inhibited PTC cell proliferation, migration, and invasion but induced apoptosis in vitro. Moreover, circLDLR acted as a sponge for miR-637, and miR-637 interference reversed the anticancer effects of circLDLR knockdown on PTC cells. LMO4 was verified to be a target of miR-637; LMO4 upregulation abolished miR-637 mediated inhibition of cell growth and metastasis in PTC. Additionally, circLDLR could indirectly modulate LMO4 via acting as a sponge of miR-637 in PTC cells. Besides that, xenograft analysis showed that circLDLR knockdown suppressed tumor growth in vivo via regulating LMO4 and miR-637. Conclusion. Taken together, these results demonstrated that circLDLR promoted PTC tumorigenesis through miR-637/LMO4 axis, which may provide a novel insight into the understanding of PTC tumorigenesis and be useful in developing potential targets for PTC treatment.


2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Oliver Podlech ◽  
Patrick N. Harter ◽  
Michel Mittelbronn ◽  
Simone Pöschel ◽  
Ulrike Naumann

In Europe, commercially available extracts from the white-berry mistletoe (Viscum albumL.) are widely used as a complementary cancer therapy. Mistletoe lectins have been identified as main active components and exhibit cytotoxic effects as well as immunomodulatory activity. Since it is still not elucidated in detail how mistle toe extracts such as ISCADOR communicate their effects, we analyzed the mechanisms that might be responsible for their antitumoral function on a molecular and functional level. ISCADOR-treated glioblastoma (GBM) cells down-regulate central genes involved in glioblastoma progression and malignancy such as the cytokine TGF-βand matrix-metalloproteinases. Usingin vitroglioblastoma/immune cell co-cultivation assays as well as measurement of cell migration and invasion, we could demonstrate that in glioblastoma cells, lectin-rich ISCADOR M and ISCADOR Q significantly enforce NK-cell-mediated GBM cell lysis. Beside its immune stimulatory effect, ISCADOR reduces the migratory and invasive potential of glioblastoma cells. In a syngeneic as well as in a xenograft glioblastoma mouse model, both pretreatment of tumor cells and intratumoral therapy of subcutaneously growing glioblastoma cells with ISCADOR Q showed delayed tumor growth. In conclusion, ISCADOR Q, showing multiple positive effects in the treatment of glioblastoma, may be a candidate for concomitant treatment of this cancer.


Tumor Biology ◽  
2017 ◽  
Vol 39 (5) ◽  
pp. 101042831769839 ◽  
Author(s):  
Bi-bo Tan ◽  
Yong Li ◽  
Li-qiao Fan ◽  
Qun Zhao ◽  
Qing-wei Liu ◽  
...  

Several studies have proved that Vav2 gene is associated with the carcinogenesis of some tumors, but the relationship between Vav2 gene and gastric cancer remains unclear. Purpose of this study is to detect the expression of Vav2 protein in gastric cancer tissues and to evaluate the clinical value of Vav2. Furthermore, both effect of Vav2 gene on invasion and metastasis of gastric cancer cells and its mechanism are investigated in vitro. Results showed that positive rate of Vav2 protein was significantly higher in gastric cancer tissues than in adjacent tissues and notably higher in metastatic lymph nodes than in gastric cancer tissues. Results of western blot were consistent with immunohistochemistry. Expression of Vav2 protein in gastric cancer tissues was related to degree of tumor differentiation, lymph node metastasis, and clinical stages. Inhibition of endogenous Vav2 in BGC823 cells led to significantly decreased cell activity, migration, and invasion ability in vitro, and expression of Rac1, MMP-2, and MMP-9 decreased, whereas expression of TIMP-1 increased. We concluded that Vav2 might promote invasion and metastasis of gastric cancer by regulating some invasion and metastasis-related genes.


2019 ◽  
Vol 26 (7) ◽  
pp. 643-658 ◽  
Author(s):  
Meng Ji ◽  
Yanli Yao ◽  
Anan Liu ◽  
Ligang Shi ◽  
Danlei Chen ◽  
...  

Pancreatic neuroendocrine neoplasms (pNENs) are endocrine tumors arising in pancreas and is the most common neuroendocrine tumors. Mounting evidence indicates lncRNA H19 could be a determinant of tumor progression. However, the expression and mechanism of H19 and the relevant genes mediated by H19 in pNENs remain undefined. Microarray analysis was conducted to identify the differentially expressed lncRNAs in pNENs. H19 expression was analyzed in 39 paired pNEN tissues by qPCR. The biological role of H19 was determined by functional experiments. RNA pulldown, mass spectroscopy and RNA immunoprecipitation were performed to confirm the interaction between H19 and VGF. RNA-seq assays were performed after knockdown H19 or VGF. H19 was significantly upregulated in pNEN tissues with malignant behaviors, and the upregulation predicted poor prognosis in pNENs. In vitro and in vivo data showed that H19 overexpression promoted tumor growth and metastasis, whereas H19 knockdown led to the opposite phenotypes. H19 interacted with VGF, which was significantly upregulated in pNENs, and higher VGF expression was markedly related to poor differentiation and advanced stage. Furthermore, VGF was downregulated when H19 was knocked down, and VGF promoted cell proliferation, migration and invasion. Mechanistic investigations revealed that H19 activated PI3K/AKT/CREB signaling and promoted pNEN progression by interacting with VGF. These findings indicate that H19 is a promising prognostic factor in pNENs with malignant behaviors and functions as an oncogene via the VGF-mediated PI3K/AKT/CREB pathway. In addition, our study implies that VGF may also serve as a candidate prognostic biomarker and therapeutic target in pNENs.


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