scholarly journals MicroRNA-935 Directly Targets FZD6 to Inhibit the Proliferation of Human Glioblastoma and Correlate to Glioma Malignancy and Prognosis

2021 ◽  
Vol 11 ◽  
Author(s):  
Dainan Zhang ◽  
Shunchang Ma ◽  
Chuanbao Zhang ◽  
Peiliang Li ◽  
Beibei Mao ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Target Genes ◽  
Bioinformatic Analysis ◽  
Glioma Cell Line ◽  
Clinical Samples ◽  
Mice Model ◽  
Human Glioblastoma ◽  
Mortality And Morbidity

MicroRNAs (miRNAs) are involved in human glioblastoma (GB). MiR-935 has been reported to have both tumor-inhibiting and tumorigenesis effects, but its role in GB remains unclear. Because of the high mortality and morbidity associated with the malignancy of GB, a deeper understanding of the molecular crosstalk that occurs in GB is needed to identify new potential targets for treatment. At present, the mechanism of GB at the molecular level is not fully understood. With the aid of bioinformatic analysis, miR-935 was significantly downregulated in GB, and it presented a poorer outcome. In the glioma cell line and in the nude mice model, the miR-935 inhibited cell proliferation by modulating cell circles in vitro and in vivo. Then, the target genes of miR-935 were analyzed by using the online database, and the direct binding was tested with a luciferase analysis. FZD6 was found to be the direct target of miR-935. The effect of miR-935 was recovered by the overexpression of FZD6 in vitro. In addition, the negative correlation of miR-935 and the expression of FZD6 were confirmed in our clinical samples, and the expression of FZD6 has a strong correlation with tumor malignancy and prognosis. This study showed that miR-935 directly inhibited the expression of FZD6 and inhibited the cell proliferation, thereby suppressing the development of GB, suggesting that miR-935 is a cancer suppressor miRNA and may become a prognostic biomarker or a promising potential therapeutic target for human GBs.

Cpne3 Regulates the Cell Proliferation and Apoptosis in Human Gbm via the Activation of Pi3k/akt Signaling Pathway

2021 ◽  
Author(s):  
Dainan Zhang ◽  
Xiaoyin Wang ◽  
Xi Wang ◽  
Zemin Wang ◽  
Shunchang Ma ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Apoptosis ◽  
Bioinformatic Analysis ◽  
Akt Pathway ◽  
Clinical Samples ◽  
Protein Markers ◽  
Mice Model ◽  
Over Expression

Abstract Background: Even with decades of intensive study, the signaling regulative network of the progression of GBM remains unclear, a deeper understanding of the molecular crosstalk with pathways in GBM is needed to identify new potential targets for treatment. Methods: To investigated the expression of CPNE3 in GBM, we applied bioinformatic analysis and clinical samples validation. Then the functional validation of carried out in commercially available glioma cell lines and nude mice model. Also, the GSEA analysis was used to identify the relevant pathways. The role of activated pathway was further validated by pharmacology method.Results: We found that CPNE3 was significantly up-regulated in GBM when compared with adjacent normal tissues, and the overexpression of CPNE3 promoted cell proliferation and inhibiting cell apoptosis in vitro and in vivo. Also, the principal protein markers of PI3K/AKT pathway were found to be phosphorylated by CPNE3 over-expression, and pathway inhibitor, LY294002, alleviated the cell proliferation enhancement induced by CPNE3 over-expression. Conclusion: Our results showed that the expression of CPNE3 promotes cell proliferation by inhibiting cell apoptosis via activating PI3K/AKT pathway, thereby enhancing the progression of GBM, which suggesting that CPNE3 may play as a tumorigenesis gene and its crosstalk with PI3K/AKT pathway may become a promising potential therapeutic target for human GBMs.

scholarly journals EGR1 Modulated LncRNA HNF1A-AS1 Drives Glioblastoma Progression Via miR-22-3p/ENO1 Axis

2021 ◽  
Author(s):  
Chunchun Ma ◽  
Hongliang Wang ◽  
Gang Zong ◽  
Jie He ◽  
Yuyang Wang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Molecular Mechanisms ◽  
Bioinformatic Analysis ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Clinical Samples ◽  
Regulation Mechanism ◽  
Functional Studies

Abstract Background: Accumulating evidences revealed that long noncoding RNAs (lncRNAs) have been participated in cancer malignant progression, including glioblastoma multiforme (GBM). Despite much studies have found the precise biological role in the regulatory mechanisms of GBM，however the molecular mechanisms，particularly upstream mechanisms still need further elucidated. Methods: RT-QPCR, cell transfection, western blotting and bioinformatic analysis were executed to detect the expression of EGR1, HNF1A-AS1, miR-22-3p and ENO1 in GBM. Cell proliferation assay, colony formation assay, wound healing, migration and invasion assays were performed to detect the malignant characters of GBM cell. The molecular regulation mechanism was confirmed by luciferase reporter assay, ChIP and RIP. Finally, orthotopic mouse models were established to examine the effect of HNF1A-AS1 in vivo.Results: In the current study, we analyzed clinical samples to show that the long non-coding antisense transcript of HNF1A, HNF1A-AS1, is upregulated and associated with poor prognosis in GBM. Functional studies revealed that knockdown of HNF1A-AS1 markedly inhibits cell proliferation, migration and invasion both in vitro and in vivo, whereas overexpression of HNF1A-AS1 exerts opposite effect. Mechanistically, the transcription factor EGR1 forced the transcription of HNF1A-AS1 by directly binding the promoter region of HNF1A-AS1. Furthermore, combined bioinformatics analysis with our mechanistic work, using luciferase reporter assays and RIP, we first demonstrated that HNF1A-AS1 functions as a competing endogenous RNA (ceRNA) with miR-22-3p to regulate ENO1 expression in GBM cells. HNF1A-AS1 directly binds to miR-22-3p and significantly inhibits miR-22-3p expression, while ENO1 expression was increased. miR-22-3p inhibitor offsets the HNF1A-AS1 silencing induced suppression in proliferation, migration and invasion of GBM cells, as well as promotion effect on ENO1 expression. ENO1 was verified as a direct target of miR-22-3p and its expression levels was negatively with the prognosis in GBM patients. Conclusion: Taken together, our study illuminated the definite mechanism of HNF1A-AS1 in promoting GBM malignancy, and provided a novel therapeutic target for further clinical application.

scholarly journals HPV-18 E6 Oncoprotein and Its Spliced Isoform E6*I Regulate the Wnt/β-Catenin Cell Signaling Pathway through the TCF-4 Transcriptional Factor

2018 ◽  
Vol 19 (10) ◽  
pp. 3153 ◽  
Author(s):  
J. Muñoz-Bello ◽  
Leslie Olmedo-Nieva ◽  
Leonardo Castro-Muñoz ◽  
Joaquín Manzo-Merino ◽  
Adriana Contreras-Paredes ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Promote Cell Proliferation ◽  
E6 And E7 ◽  
Hpv 18

The Wnt/β-catenin signaling pathway regulates cell proliferation and differentiation and its aberrant activation in cervical cancer has been described. Persistent infection with high risk human papillomavirus (HR-HPV) is the most important factor for the development of this neoplasia, since E6 and E7 viral oncoproteins alter cellular processes, promoting cervical cancer development. A role of HPV-16 E6 in Wnt/β-catenin signaling has been proposed, although the participation of HPV-18 E6 has not been previously studied. The aim of this work was to investigate the participation of HPV-18 E6 and E6*I, in the regulation of the Wnt/β-catenin signaling pathway. Here, we show that E6 proteins up-regulate TCF-4 transcriptional activity and promote overexpression of Wnt target genes. In addition, it was demonstrated that E6 and E6*I bind to the TCF-4 (T cell factor 4) and β-catenin, impacting TCF-4 stabilization. We found that both E6 and E6*I proteins interact with the promoter of Sp5, in vitro and in vivo. Moreover, although differences in TCF-4 transcriptional activation were found among E6 intratype variants, no changes were observed in the levels of regulated genes. Furthermore, our data support that E6 proteins cooperate with β-catenin to promote cell proliferation.

scholarly journals Circular RNA CDR1as Exerts Oncogenic Properties Partially through Regulating MicroRNA 641 in Cholangiocarcinoma

2020 ◽  
Vol 40 (15) ◽  
Author(s):  
Dingyang Li ◽  
Zhe Tang ◽  
Zhiqiang Gao ◽  
Pengcheng Shen ◽  
Zhaochen Liu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Target Genes ◽  
Circular Rna ◽  
Tumor Xenograft ◽  
Mrna Levels ◽  
Cell Behaviors ◽  
Xenograft Growth ◽  
Tumor Xenograft Growth

ABSTRACT It has been found that the circular RNA (circRNA) CDR1as is upregulated in cholangiocarcinoma (CCA) tissues. In this study, we tried to explore the roles of CDR1as in CCA. CDR1as was overexpressed or knocked down in human CCA cells to assess the effects of CDR1as on cell behaviors and tumor xenograft growth. In vitro, the CDR1as level was significantly increased in CCA cell lines. The results showed that CDR1as promoted the cell proliferation, migration, invasion, and activation of the AKT3/mTOR pathway in CCA cells. Moreover, miR-641, a predicted target microRNA (miRNA) of CDR1as, could partially reverse the effects of CDR1as on cell behaviors in CCA cells. Furthermore, CDR1as improved tumor xenograft growth, and it could be attenuated by miR-641 in vivo. Additionally, CDR1as expression was inversely correlated with miR-641 in CCA cells, and miR-641 could directly bind with CDR1as and its target genes, the AKT3 and mTOR genes. Mechanistically, CDR1as could bind with miR-641 and accelerate miR-641 degradation, which possibly leads to the upregulation of the relative mRNA levels of AKT3 and mTOR in RBE cells. In conclusion, our findings indicated that CDR1as might exert oncogenic properties, at least partially, by regulating miR-641 in CCA. CDR1as and miR-641 could be considered therapeutic targets for CCA.

scholarly journals AXL and CAV-1 play a role for MTH1 inhibitor TH1579 sensitivity in cutaneous malignant melanoma

2020 ◽  
Vol 27 (7) ◽  
pp. 2081-2098 ◽  
Author(s):  
Ishani Das ◽  
Helge Gad ◽  
Lars Bräutigam ◽  
Linda Pudelko ◽  
Rainer Tuominen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Cell Death ◽  
Malignant Melanoma ◽  
Braf Inhibitor ◽  
Mitotic Arrest ◽  
Cutaneous Malignant Melanoma ◽  
Clinical Samples

AbstractCutaneous malignant melanoma (CMM) is the deadliest form of skin cancer and clinically challenging due to its propensity to develop therapy resistance. Reactive oxygen species (ROS) can induce DNA damage and play a significant role in CMM. MTH1 protein protects from ROS damage and is often overexpressed in different cancer types including CMM. Herein, we report that MTH1 inhibitor TH1579 induced ROS levels, increased DNA damage responses, caused mitotic arrest and suppressed CMM proliferation leading to cell death both in vitro and in an in vivo xenograft CMM zebrafish disease model. TH1579 was more potent in abrogating cell proliferation and inducing cell death in a heterogeneous co-culture setting when compared with CMM standard treatments, vemurafenib or trametinib, showing its broad anticancer activity. Silencing MTH1 alone exhibited similar cytotoxic effects with concomitant induction of mitotic arrest and ROS induction culminating in cell death in most CMM cell lines tested, further emphasizing the importance of MTH1 in CMM cells. Furthermore, overexpression of receptor tyrosine kinase AXL, previously demonstrated to contribute to BRAF inhibitor resistance, sensitized BRAF mutant and BRAF/NRAS wildtype CMM cells to TH1579. AXL overexpression culminated in increased ROS levels in CMM cells. Moreover, silencing of a protein that has shown opposing effects on cell proliferation, CAV-1, decreased sensitivity to TH1579 in a BRAF inhibitor resistant cell line. AXL-MTH1 and CAV-1-MTH1 mRNA expressions were correlated as seen in CMM clinical samples. Finally, TH1579 in combination with BRAF inhibitor exhibited a more potent cell killing effect in BRAF mutant cells both in vitro and in vivo. In summary, we show that TH1579-mediated efficacy is independent of BRAF/NRAS mutational status but dependent on the expression of AXL and CAV-1.

scholarly journals PHF14 Promotes Cell Proliferation and Migration through the AKT and ERK1/2 Pathways in Gastric Cancer Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Yuzu Zhao ◽  
Jiang He ◽  
Yongsen Li ◽  
Man Xu ◽  
Xingzhi Peng ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Tumor Development ◽  
Tumor Promoter ◽  
Clinical Samples ◽  
Gastric Cancer Cells ◽  
Phosphorylated Akt

PHF14 is a new member belonging to PHD finger proteins. PHF14 is involved in multiple biologic processes including Dandy–Walker syndrome, mesenchyme growth, lung fibrosis, renal fibrosis, persistent pulmonary hypertension, and tumor development. This study aims to explore whether PHF14 plays an important role in gastric cancer. Here, PHF14 is indicated as a tumor promoter. The expression of PHF14 enhances no matter in clinical samples or in gastric cancer cells. High expression of PHF14 impairs survival of patients. Attenuation of PHF14 inhibits cell proliferation in gastric cancer cells. PHF14 downregulation inhibits the expression of cell cycle-related proteins, CDK6 and cyclin D1. Furthermore, silencing of PHF14 reduces the level of phosphorylated AKT as well as phosphorylated ERK1/2. Finally, downregulation of PHF14 in gastric cancer cells inhibits colony formation in vitro and tumorigenesis in vivo. These results indicate that PHF14 promotes tumor development in gastric cancer, so PHF14 thereby acts as a potential target for gastric cancer therapy.

scholarly journals Metformin Inhibited Proliferation and Metastasis of Colorectal Cancer and presented a Synergistic Effect on 5-FU

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Jing Sang ◽  
Ruixue Tang ◽  
Min Yang ◽  
Qing Sun
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Synergistic Effect ◽  
Nude Mice ◽  
Mice Model ◽  
Proliferation And Metastasis ◽  
Tumor Growth And Metastasis ◽  
Proliferation And Invasion

The purpose of this study was to investigate the effect of metformin or the combination of metformin and 5-FU on the growth and metastasis of colorectal cancer (CRC). For the in vitro experiments, HCT 116 and SW1463 cell lines were treated with metformin or the combination of metformin and 5-FU. Cell proliferation and invasion were analyzed by CCK-8, colony formation, and transwell assay, respectively. For the in vivo experiments, the CRC xenograft nude mice model was used to observe the effects of metformin or combined with 5-FU on tumor growth and metastasis. Metformin significantly inhibited the proliferation and invasion of HCT116 and SW1463 cells in vitro, which showed synergetic effects to 5-FU. In CRC xenograft nude mice, metformin alone and metformin combined with 5-FU treatment significantly inhibited tumor cell proliferation and tumor metastasis. In summary, metformin played an inhibitory role in the proliferation and metastasis of CRC and had a synergistic effect with 5-FU. Metformin may be a potentially effective anti-metastatic drug or an anticancer adjuvant agent for treating CRC.

scholarly journals Glaucocalyxin A suppresses multiple myeloma progression in vitro and in vivo through inhibiting the activation of STAT3 signaling pathway

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Mei Li ◽  
Cailong Chen ◽  
Qian Wang ◽  
Xiaolu Jiang ◽  
Lanlan Tan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Xenograft Model ◽  
Mice Model ◽  
Cycle Arrest ◽  
Nude Mice Model

Abstract Background Multiple myeloma (MM) is the most common malignant hematological disease in the people worldwide. Glaucocalyxin A (GLA) is a bioactive ent-kauranoid diterpenoid, that is derived from Rabdosia japonica var. GLA has been demonstrated that it had various pharmacological activities, such as anti-coagulation, anti-bacterial, anti-tumor, anti-inflammation, antioxidant activities. Although GLA has effective anti-tumor properties, its effects on multiple myeloma remain unclear. The aim of this study was to examine the possible anti-cancer effects of GLA and their molecular mechanisms on MM cells in vitro and in vivo. Methods To evaluate the role of GLA on the proliferation of MM cells in vitro and in vivo, we used MTT method to detect the role of GLA on the proliferation of MM cells. Cell apoptosis and cell cycle assay were evaluated by flow cytometry. Protein expressions in GLA-treated and untreated MM cells were evaluated by western blot analyses. MM xenograft nude mice model was used to investigate the role of GLA on the proliferation of MM cells in vivo. IHC assay was used to examine the role of GLA on the MM xenograft model in vivo. Results In the present study, we firstly reported the potent anti-myeloma activity of GLA on MM cells. We found that GLA could induce apoptosis in vitro and in vivo. GLA could inhibit the phosphorylation of the signal transducer and activator of transcription 3 (STAT3) and downregulate interleukin IL-6 induced STAT3 phosphorylation in MM. Overexpression of STAT3 could significantly prevent apoptosis induced by GLA; while knockdown of STAT3 enhanced it. Moreover, GLA could inhibit cell proliferation by inducing the cell cycle arrest. GLA reduced the expression of cell cycle-related proteins CCNB1, CCND1, CCND2, and CCND3 and increased the expression of p21 in MM cell lines. In addition, in the MM xenograft nude mice model, GLA exhibited very good anti-myeloma activity. Administration of GLA almost completely inhibited tumor growth within 19 days without physical toxicity. And the IHC results showed GLA significantly inhibited cell proliferation and interfered STAT3 pathway on MM xenograft model tumor tissues. Conclusions Taken together, our present research indicated that GLA inhibits the MM cell proliferation, induces MM cell apoptosis and cell cycle arrest through blocking the activation of STAT3 pathway. Thus, GLA may be a potential therapeutic candidate for MM patients in the future.

scholarly journals Down-regulated HSDL2 expression suppresses cell proliferation and promotes apoptosis in papillary thyroid carcinoma

2019 ◽  
Vol 39 (6) ◽  
Author(s):  
Jing Zeng ◽  
Xiao Ma ◽  
Jinjing Wang ◽  
Ran Liu ◽  
Yun Shao ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Target Genes ◽  
Mrna Level ◽  
Papillary Thyroid ◽  
Bioinformatics Analyses ◽  
In Vivo Experiments

Abstract Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Hydroxysteroid dehydrogenase like 2 (HSDL2) can regulate lipid metabolism and take part in cell proliferation. The purpose of the present study was to explore functional role of HSDL2 gene in PTC. The expression of HSDL2 protein in PTC tissues was estimated using immunohistochemistry analysis (IHC). HSDL2 mRNA level was detected through quantitative real-time polymerase chain reaction (qRT-PCR). Effects of HSDL2 gene on cell proliferation and apoptosis were assessed using the shRNA method for both in vitro and in vivo experiments. Potential target genes of HSDL2 were determined via bioinformatics analyses and Western blotting. HSDL2 was up-regulated in PTC tissues and cell lines compared with the controls (all P<0.05). Inhibiting HSDL expression could suppress PTC cell proliferation and cycle, and promote apoptosis in vitro. In vivo, the knockdown of HSDL2 gene could significantly suppress tumor growth (all P<0.05). Furthermore, AKT3, NFATc2 and PPP3CA genes might be potential targets of HSDL2 in PTC. HSDL2 expression was increased in PTC tissues and cells, which could promote tumor progression in vitro and in vivo.

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