ETV5-mediated upregulation of lncRNA CTBP1-DT as a ceRNA facilitates HGSOC progression by regulating miR-188-5p/MAP3K3 axis

AbstractHigh-grade serous ovarian cancer (HGSOC) is a common and lethal cancer of the female reproductive system. Long non-coding RNAs (lncRNAs) are aberrantly expressed in various cancers and play crucial roles in tumour progression. However, their function and molecular mechanism in HGSOC remain largely unknown. Based on public databases and bioinformatics analyses, the overexpression of lncRNA CTBP1-DT in HGSOC tissues was detected and validated in a cohort of HGSOC tissues. High expression of lncRNA CTBP1-DT was associated with poor prognosis and was an independent risk factor for survival. Overexpression of lncRNA CTBP1-DT promoted malignant biological behaviour of HGSOC cells, whereas its depletion induced growth arrest of HGSOC cells by vitro and in vivo assays. Mechanistically, lncRNA CTBP1-DT could competitively bind to miR-188-5p to protect MAP3K3 from degradation. Moreover, our results revealed that ETV5 could specifically interact with the promoter of lncRNA CTBP1-DT and activate its transcription. Collectively, these results reveal a novel ETV5/lncRNA CTBP1-DT/miR-188-5p/MAP3K3 pathway for HGSOC progression and suggest that lncRNA CTBP1-DT might be a potential biomarker and therapeutic target for HGSOC.

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PLEKHA8P1 Promotes Tumor Progression and Indicates Poor Prognosis of Liver Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22147614 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7614

Author(s):

Jiyeon Lee ◽

Ji-Hyun Hwang ◽

Harim Chun ◽

Wonjin Woo ◽

Sekyung Oh ◽

...

Keyword(s):

Liver Cancer ◽

Tumor Progression ◽

Poor Prognosis ◽

Prognostic Value ◽

Experimental Validation ◽

Bioinformatics Analyses ◽

New Class ◽

Parental Gene ◽

Non Coding Rnas ◽

Regulatory Landscape

Hepatocellular carcinoma (HCC) records the second-lowest 5-year survival rate despite the avalanche of research into diagnosis and therapy. One of the major obstacles in treatment is chemoresistance to drugs such as 5-fluorouracil (5-FU), making identification and elucidation of chemoresistance regulators highly valuable. As the regulatory landscape grows to encompass non-coding genes such as long non-coding RNAs (lncRNAs), a relatively new class of lncRNA has emerged in the form of pseudogene-derived lncRNAs. Through bioinformatics analyses of the TCGA LIHC dataset, we have systematically identified pseudogenes of prognostic value. Initial experimental validation of selected pseudogene-derived lncRNA (PLEKHA8P1) and its parental gene (PLEKHA8), a well-studied transport protein in Golgi complex recently implicated as an oncogene in both colorectal and liver cancer, indicates that the pseudogene/parental gene pair promotes tumor progression and that their dysregulated expression levels affect 5-FU-induced chemoresistance in human HCC cell line FT3-7. Our study has thus confirmed cancer-related functions of PLEKHA8, and laid the groundwork for identification and validation of oncogenic pseudogene-derived lncRNA that shows potential as a novel therapeutic target in circumventing chemoresistance induced by 5-FU.

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TDO2 Was Downregulated in Hepatocellular Carcinoma and Inhibited Cell Proliferation by Upregulating the Expression of p21 and p27

BioMed Research International ◽

10.1155/2021/4708439 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Chengpeng Yu ◽

Dean Rao ◽

He Zhu ◽

Qiumeng Liu ◽

Wenjie Huang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Cycle ◽

Cell Proliferation ◽

Clinical Outcomes ◽

Poor Prognosis ◽

Kynurenine Pathway ◽

Potential Biomarker ◽

In Vivo Flow Cytometry

Background. Tryptophan-2,3-dioxygenase (TDO2) converts tryptophan into kynurenine in the initial limiting step of the kynurenine pathway. During the past decade, the overexpression of TDO2 has been found in various human tumors. However, the role of TDO2 in hepatocellular carcinoma is controversial, and we sought to clarify it in this study. Methods. Western blot analysis and immunochemistry were used to detect the expression of TDO2 in human tissue specimens. The effect of TDO2 on cell proliferation in vitro was assessed using CCK8 and colony formation assays, and a xenograft mouse model was used to detect the effect of TDO2 on tumor growth in vivo. Flow cytometry was used to assess the cell cycle status. Results. Low TDO2 expression was found in HCC and was associated with poor prognosis and adverse clinical outcomes. Conversely, TDO2 could restrain the proliferation of HCC cells in vivo and in vitro. Furthermore, TDO2 upregulated the expression of p21 and p27, inducing cell-cycle arrest. Conclusions. The loss of TDO2 expression in HCC was correlated with a poor prognosis and adverse clinical outcomes. At the same time, TDO2 could restrain the growth of HCC in vivo and in vitro. The results indicate that TDO2 is a potential biomarker and therapeutic target for HCC.

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The FENDRR/FOXC2 Axis Contributes to Multidrug Resistance in Gastric Cancer and Correlates With Poor Prognosis

Frontiers in Oncology ◽

10.3389/fonc.2021.634579 ◽

2021 ◽

Vol 11 ◽

Author(s):

Hao Liu ◽

Zhe Zhang ◽

Yanan Han ◽

Ahui Fan ◽

Haiming Liu ◽

...

Keyword(s):

Gastric Cancer ◽

Multidrug Resistance ◽

Poor Prognosis ◽

Clinical Samples ◽

Regulatory Interactions ◽

Non Coding Rnas ◽

New Perspective

The dysregulation of long non-coding RNAs (lncRNAs) and transcription factors (TFs) is closely related to the development and progression of drug resistance in cancer chemotherapy. However, their regulatory interactions in the multidrug resistance (MDR) of gastric cancer (GC) has largely remained unknown. In this study, we report a novel oncogenic role of lncRNA FENDRR in conferring MDR in GC by coordinated regulation of FOXC2 expression at the transcriptional and posttranscriptional levels. In vitro and in vivo experiments demonstrated that downregulation of FENDRR expression remarkably decreased drug resistant ability of GC MDR cells while upregulation of FENDRR expression produced the opposite effect. FENDRR overexpression was observed in MDR GC cell lines, patient-derived xenografts, and clinical samples. And the high levels of FENDRR expression were correlated with poor prognosis in GC patients. Regarding the mechanism, FENDRR was revealed to increase proto-oncogene FOXC2 transcription by performing an enhancer-like role in the nucleus and by sponging miR-4700-3p in the cytoplasm. Both FOXC2 and miR-4700-3p were shown to be functionally involved in the FENDRR-induced chemoresistance. In addition, there is a positive correlation between FENDRR and FOXC2 expression in clinic and the overexpressed FOXC2 indicated a poor prognosis in GC patients. Collectively, our findings provide a new perspective for the lncRNA-TF regulatory interaction involved in MDR, suggesting that targeting the FENDRR/FOXC2 axis may be an effective approach to circumvent GC chemoresistance.

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NcRNAs-mediated High Expression of TIMM8A Correlates with Poor Prognosis and Act as an Oncogene in Breast Cancer

10.21203/rs.3.rs-1079496/v1 ◽

2021 ◽

Author(s):

Zhonglin Wang ◽

Shuqin Li ◽

Feng Xu ◽

Jingyue Fu ◽

Jie Sun ◽

...

Keyword(s):

Breast Cancer ◽

Poor Prognosis ◽

Molecular Mechanisms ◽

Human Cancer ◽

Luciferase Reporter ◽

Inner Mitochondrial Membrane ◽

Cancer Proliferation ◽

Bioinformatics Analyses

Abstract Background: Breast cancer is notorious for its increasing incidence for decades. Ascending evidence has demonstrated that translocase of inner mitochondrial membrane (TIMM) proteins play vital roles in progression of several types of human cancer. However, the biological behaviors and molecular mechanisms of TIMM8A in breast cancer remain not fully illustrated.Methods: Pan-cancer analysis was firstly performed for TIMM8A’s expression and prognosis by Oncomine database. Subsequently, TIMM8A-related noncoding RNAs (ncRNAs) were identified by a series of bioinformatics analyses and dual-luciferase reporter assay, including expression analysis, correlation analysis, and survival analysis. Moreover, the effect of TIMM8A on breast cancer proliferation and apoptosis was evaluated in vitro by CCK-8 assays, colony formation assays and Western blot assays and the in vivo effect was revealed through a patient-derived xenograft mouse model.Results: We found that TIMM8A showed higher expression level in breast cancer and the higher TIMM8A mRNA expression group had a poorer prognosis than the lower TIMM8A group. hsa-circ-0107314/hsa-circ-0021867/hsa-circ-0122013 might be the three most potential upstream circRNAs of hsa-miR-34c-5p/hsa-miR-449a-TIMM8A axis in breast cancer. TIMM8A promotes proliferation of breast cancer cells in vitro and tumor growth in vivo.Conclusion: Our results confirmed that ncRNAs-mediated upregulation of TIMM8A correlated with poor prognosis and act as an oncogene in breast cancer.

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Downregulation of PRAME Suppresses Proliferation and Promotes Apoptosis in Hepatocellular Carcinoma Through the Activation of P53 Mediated Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000487353 ◽

2018 ◽

Vol 45 (3) ◽

pp. 1121-1135 ◽

Cited By ~ 9

Author(s):

Hanzhang Zhu ◽

Jingrui Wang ◽

Junjie Yin ◽

Bei Lu ◽

Qijun Yang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Lines ◽

Therapeutic Target ◽

Cell Apoptosis ◽

Poor Prognosis ◽

P53 Pathway ◽

Tissue Samples ◽

Potential Biomarker

Background/Aims: The expression of PRAME and its role in hepatocellular carcinoma (HCC) remain unknown. The aim of this study was to examine the functional role of PRAME in HCC development and exploring the molecular mechanism. Methods: We first detected PRAME expression in 96 human HCC tissue samples and correlated with clinicopathological characteristics and prognosis of the patients. We then established stable HCC cell lines with PRAME overexpression and knockdown followed by functional analysis in vitro. Further, we examined the relationship between PRAME and p53 pathway in vitro by using Western blotting. Finally, PRAME expression was detected to evaluate its correlation with p-p53 and p53 pathway related apoptotic proteins in xenograft tumor mouse model using immunohistochemistry. Results: PRAME expression was significantly higher in HCC tissues than in adjacent non-tumor tissues and their expression was positively correlated with alpha fetoprotein levels and tumor size. In addition, PRAME expression was associated with AJCC stage and is a potential biomarker of poor prognosis regarding 5-year overall survival in HCC. In vitro studies, we found that PRAME expression was higher in HCC cell lines than in normal hepatic cell line. Inhibited cell proliferation and increased cell apoptosis was observed in PRAME knockdown HCC cells. Futher, increased cell apoptosis was correlated with the proportion of cells in G0/G1 stage, activated p53 mediated apoptosis, and increased cyclin p21 expression. Xenograft analysis in nude mice also found that PRAME knockdown inhibited tumorigenesis while PRAME overexpression had opposite effect. Conclusions: In HCC, PRAME serves as a potential biomarker for poor prognosis and novel therapeutic target in treating this cancer. PRAME is a potential biomarker of poor prognosis in HCC. PRAME surpresses HCC cell death in vitro and in vivo by regulating p53 apoptotic signaling and may serve as a potential therapeutic target in HCC.

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TGF-β1 Induced Deficiency of Linc00261 Promotes Epithelial-mesenchymal-transition and Stemness of Hepatocellular Carcinoma via Modulating SMAD3

10.21203/rs.3.rs-986336/v1 ◽

2021 ◽

Author(s):

Zhanjun Chen ◽

Leyang Xiang ◽

Huohui Ou ◽

Yinghao Fang ◽

Yuyan Xu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Poor Prognosis ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Tumor Sphere ◽

Non Coding Rnas ◽

Tgf Β1 ◽

Hcc Cells

Abstract Emerging evidence suggests that long non-coding RNAs (lncRNAs) play important roles in the metastasis and recurrence of hepatocellular carcinoma (HCC).Kinds of lncRNAs were found to be involved in regulating epithelial-mesenchymal transition (EMT) or stem-like traits in human cancers, however, the molecular mechanism and signaling pathways targeting EMT and stemness remains largely unknown. Previously, we found that linc00261 was down-regulated in HCC and associated with multiple worse clinic pathological parameters and poor prognosis. Here, we show that linc00261 was down-regulated in TGF-β1 stimulated cells, and forced expression of linc00261 attenuated EMT and stem-like traits in HCC.Linc00261 also inhibited the tumor sphere forming in vitro and decreased the tumorigenicity in vivo. Furthermore, we revealed that linc00261 suppressed the expression and phosphorylation of SMAD3 (p-SMAD3), which is a core transcriptional modulator in TGF-β1 signaling mediated EMT and the acquisition of stemness traits. A negative correlation between linc00261 and p-SMAD3 was determined in HCC samples.Conclusion: Our study revealed that linc00261suppressed EMT and stem-like traits of HCC cells by inhibiting TGF-β1/SMAD3 signaling.

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Evidence of oncogene-induced senescence in thyroid carcinogenesis

Endocrine Related Cancer ◽

10.1530/erc-11-0240 ◽

2011 ◽

Vol 18 (6) ◽

pp. 743-757 ◽

Cited By ~ 29

Author(s):

Maria Grazia Vizioli ◽

Patricia A Possik ◽

Eva Tarantino ◽

Katrin Meissl ◽

Maria Grazia Borrello ◽

...

Keyword(s):

Kinase Inhibitors ◽

Tumour Progression ◽

Growth Arrest ◽

Immunohistochemical Analysis ◽

Cyclin Dependent Kinase ◽

Thyroid Tumour ◽

Thyroid Epithelium

Oncogene-induced senescence (OIS) is a growth arrest triggered by the enforced expression of cancer-promoting genes and acts as a barrier against malignant transformation in vivo. In this study, by a combination of in vitro and in vivo approaches, we investigate the role of OIS in tumours originating from the thyroid epithelium. We found that expression of different thyroid tumour-associated oncogenes in primary human thyrocytes triggers senescence, as demonstrated by the presence of OIS hallmarks: changes in cell morphology, accumulation of SA-β-Gal and senescence-associated heterochromatic foci, and upregulation of transcription of the cyclin-dependent kinase inhibitors p16INK4a and p21CIP1. Furthermore, immunohistochemical analysis of a panel of thyroid tumours characterised by different aggressiveness showed that the expression of OIS markers such as p16INK4a, p21CIP1 and IGFBP7 is upregulated at early stages, and lost during thyroid tumour progression. Taken together, our results suggest a role of OIS in thyroid carcinogenesis.

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Interfering with long non-coding RNA MIR22HG processing inhibits glioblastoma progression through suppression of Wnt/β-catenin signalling

Brain ◽

10.1093/brain/awz406 ◽

2019 ◽

Vol 143 (2) ◽

pp. 512-530 ◽

Cited By ~ 10

Author(s):

Mingzhi Han ◽

Shuai Wang ◽

Sabrina Fritah ◽

Xu Wang ◽

Wenjing Zhou ◽

...

Keyword(s):

Tumour Growth ◽

Tumour Progression ◽

3D Structure ◽

Signalling Pathway ◽

Functional Studies ◽

Non Coding Rna ◽

Molecule Inhibitor ◽

Non Coding Rnas ◽

The Impact

Abstract Long non-coding RNAs play critical roles in tumour progression. Through analysis of publicly available genomic datasets, we found that MIR22HG, the host gene of microRNAs miR-22-3p and miR-22-5p, is ranked among the most dysregulated long non-coding RNAs in glioblastoma. The main purpose of this work was to determine the impact of MIR22HG on glioblastoma growth and invasion and to elucidate its mechanistic function. The MIR22HG/miR-22 axis was highly expressed in glioblastoma as well as in glioma stem-like cells compared to normal neural stem cells. In glioblastoma, increased expression of MIR22HG is associated with poor prognosis. Through a number of functional studies, we show that MIR22HG silencing inhibits the Wnt/β-catenin signalling pathway through loss of miR-22-3p and -5p. This leads to attenuated cell proliferation, invasion and in vivo tumour growth. We further show that two genes, SFRP2 and PCDH15, are direct targets of miR-22-3p and -5p and inhibit Wnt signalling in glioblastoma. Finally, based on the 3D structure of the pre-miR-22, we identified a specific small-molecule inhibitor, AC1L6JTK, that inhibits the enzyme Dicer to block processing of pre-miR-22 into mature miR-22. AC1L6JTK treatment caused an inhibition of tumour growth in vivo. Our findings show that MIR22HG is a critical inducer of the Wnt/β-catenin signalling pathway, and that its targeting may represent a novel therapeutic strategy in glioblastoma patients.

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CircVAPA promotes proliferation and metastasis of retinoblastoma by modulating miR-615-3p and SMARCE1

10.21203/rs.3.rs-20759/v1 ◽

2020 ◽

Author(s):

Qibin Xu

Keyword(s):

Flow Cytometry ◽

Cancer Development ◽

Circular Rnas ◽

Malignant Phenotype ◽

In Vivo Assays ◽

Potential Biomarker ◽

Proliferation And Metastasis ◽

In Vivo Analysis ◽

Poor Outcomes

Abstract Background Growing evidence reveals that circular RNAs (circRNAs) play roles in cancer development. However, the effects and possible mechanisms of circRNAs in retinoblastoma (RB) are far from clear. Methods circVAPA expression pattern was identified by RT-qPCR. CircVAPA induced effects on RB cells were tested by CCK-8, clone forming, flow cytometry and transwell assays. Bioinformatics assay, rescue experiments and dual luciferase tests were applied for mechanism exploration. Additionally, mouse models were established for in vivo assays. Results circVAPA was expressed at high levels in human RB specimen and RB cell lines, and was correlated with poor outcomes of Rb patients. Knockdown of circVAPA could suppress the malignant phenotype of RB. Mechanistic experiments demonstrated that miR-615-3p could reverse the circVAPA induced effects on RB cells, and the downstream oncogene SMARCE1 was positively regulated by circVAPA via miR-615-3p. Further, in vivo analysis confirmed the findings. Conclusions In summary, circVAPA promoted RB proliferation and metastasis by sponging miR-615-3p, thereby upregulating SMARCE1. CircVAPA is a potential biomarker of Rb therapy.

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RBM8A promotes growth and invasion through the Notch/STAT3 pathway in glioblastoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e14038 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e14038-e14038

Author(s):

Yan Lin ◽

Jinyan Zhang ◽

Beiquan Hu ◽

Gang Qin ◽

Rong Liang ◽

...

Keyword(s):

Cell Proliferation ◽

Poor Prognosis ◽

Glioblastoma Cell ◽

Stat3 Pathway ◽

In Vivo Assays ◽

Cell Proliferation And Migration ◽

And Migration ◽

Proliferation And Migration

e14038 Background: Glioblastoma (GBM) is a prevalent brain malignance with an extremely poor prognosis, which is attributable to its invasive biological behaviors. The RNA-binding motif protein 8A (RBM8A) has different effects on various human cancers. However, the implication of RBM8A in glioblastoma progression remains unclear. Methods: Glioblastoma (GBM) data set was downloaded from the Cancer Genome Atlas (TCGA). Differential expression analysis was used to screen the differentially expressed genes (DEGs) between GBM and control, RBM8A high and low expression samples, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Gene Genomes (KEGG) analysis were performed on the co-upregulated DEGs. Additionally, We investigated the expression levels of RBM8A in 94 glioblastoma patients and explored the correlation between the RBM8A expressions with prognosis. Using in vitro and in vivo assays, we addressed the functional impacts of RBM8A on and the underlying mechanisms through which RBM8A contribute to glioblastoma progression. In addition, a comprehensive regulatory network of RBM8A regulation was constructed based on STRING database. Molecular docking model was used to predict the possibility of RBM8A binding to target genes. Combined with TCGA and Chinese glioma genome map (CGGA), gene set variance analysis (GSVA) was used to calculate the GSVA scores of the genes involved in the mechanism. Receiver operator characteristic curve (ROC) curve analysis and survival analysis were performed to explore the prognostic and diagnostic ability of GSVA score for GBM. Results: Our results indicate that higher RBM8A expression in glioblastoma tissues was associated with a poor prognosis. In addition, functional enrichment analysis based on genes related to RBM8A expression showed that RBM8A was related to cell cycle and Notch signaling pathway. RBM8A may promote glioblastoma cell proliferation and migration by activating Notch/STAT3 pathway in glioblastoma cells. In vitro and in vivo assays confirmed that knocking down RBM8A inhibited glioblastoma progression and invasion ability. We also observed that the pro-oncogenic effects of RBM8A in glioblastoma tissues were mediated by activation of the Notch/STAT3 pathway. Finally, it was concluded that the GSVA score has good diagnostic and prognostic value for GBM. Conclusions: RBM8A may promote glioblastoma cell proliferation and migration by activating Notch/STAT3 pathway in glioblastoma cells, suggesting that RBM8A may serve as a potential therapeutic target for the treatment of glioblastoma.

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