scholarly journals Human Schlafen 5 Inhibits Proliferation and Promotes Apoptosis in Lung Adenocarcinoma via the PTEN/PI3K/AKT/mTOR Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Xuefeng Gu ◽  
Li Zhou ◽  
Lei Chen ◽  
Huiqing Pan ◽  
Rui Zhao ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Lung Adenocarcinoma ◽  
Signaling Pathway ◽  
Xenograft Model ◽  
Immunohistochemical Analysis ◽  
Mtor Pathway ◽  
Protein Levels ◽  
Mouse Xenograft Model

Background. Human Schlafen 5 (SLFN5) is reported to inhibit or promote the proliferation of several specific types of cancer cells by our lab and other researchers. We are curious about its implications in lung adenocarcinoma (LUAC), a malignant tumor with a high incidence rate and high mortality. Method. Lentiviral stable transfections of SLFN5-specific shRNA for knockdown and SLFN5 full-length coding sequence for overexpression were performed in LUAC cell for proliferation analysis in vitro and in vivo in nude mice. Clinical LUAC samples were collected for immunohistochemical analysis of SLFN5 protein levels. Results. We found that knockdown of endogenous SLFN5 upregulates cancer cell proliferation while inhibiting apoptosis. Besides, SLFN5 inhibition on proliferation was also observed in a nude mouse xenograft model. In contrast, overexpression of exogenous SLFN5 inhibited cell proliferation in vitro and in vivo and promoted apoptosis. As to the signaling pathway, we found phosphatase and tensin homolog on chromosome 10 (PTEN) was positively regulated by SLFN5, while its downstream signaling pathway AKT/mammalian target of rapamycin (mTOR) was inhibited. Moreover, compared with adjacent normal tissues, SLFN5 protein levels were markedly decreased in lung adenocarcinoma tissues. In conclusion, these suggest that human SLFN5 plays inhibitory roles in LUAC progression through the PTEN/PI3K/AKT/mTOR pathway, providing a potential target for developing drugs for lung cancer therapy in the future.

scholarly journals MNAT1 promotes proliferation and the chemo-resistance of osteosarcoma cell to cisplatin through regulating PI3K/Akt/mTOR pathway

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Chensheng Qiu ◽  
Weiliang Su ◽  
Nana Shen ◽  
Xiaoying Qi ◽  
Xiaolin Wu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Xenograft Model ◽  
Mtor Pathway ◽  
Regulation Mechanism ◽  
Osteosarcoma Cell ◽  
Migration Ability ◽  
Mouse Xenograft Model

Abstract Background MNAT1 (menage a trois 1, MAT1), a cyclin-dependent kinase-activating kinase (CAK) complex, highly expressed in diverse cancers and was involved in cancer molecular pathogenesis. However, its deliverance profile and biological function in osteosarcoma (OS) remain unclear. Methods The expression of MNAT1 in OS was detected by western blot (WB) and immunohistochemistry (IHC). The potential relationship between MNAT1 molecular level expression and OS clinical expectations were analyzed according to tissues microarray (TMA). Proliferation potential of OS cells was evaluated in vitro based on CCK8 and OS cells colony formation assays, while OS cells transwell and in situ tissue source wound healing assays were employed to analyze the OS cells invasion and migration ability in vitro. A nude mouse xenograft model was used to detect tumor growth in vivo. In addition, ordinary bioinformatics analysis and experimental correlation verification were performed to investigate the underlying regulation mechanism of OS by MNAT1. Results In this research, we found and confirmed that MNAT1 was markedly over-expressed in OS tissue derived in situ, also, highly MNAT1 expression was closely associated with bad clinical expectations. Functional studies had shown that MNAT1 silencing could weaken the invasion, migration and proliferation of OS cells in vitro, and inhibit OS tumor growth in vivo. Mechanism study indicated that MNAT1 contributed to the progression of OS via the PI3K/Akt/mTOR pathway. We further verified that the MNAT1 was required in the regulation of OS chemo-sensitivity to cisplatin (DDP). Conclusions Taken together, the data of the present study demonstrate a novel molecular mechanism of MNAT1 involved in the formation of DDP resistance of OS cells.

scholarly journals The endocannabinoid anandamide inhibits cholangiocarcinoma growth via activation of the noncanonical Wnt signaling pathway

2008 ◽  
Vol 295 (6) ◽  
pp. G1150-G1158 ◽  
Author(s):  
Sharon DeMorrow ◽  
Heather Francis ◽  
Eugenio Gaudio ◽  
Julie Venter ◽  
Antonio Franchitto ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Calcium Release ◽  
Wnt Signaling Pathway ◽  
Xenograft Model ◽  
Orphan Receptor

Cholangiocarcinomas are cancers that have poor prognosis and limited treatment options. The noncanonical Wnt pathway is mediated predominantly by Wnt 5a, which activates a Ca2+-dependent pathway involving protein kinase C, or a Ca2+-independent pathway involving the orphan receptor Ror2 and subsequent activation of Jun NH2-terminal kinase (JNK). This pathway is associated with growth-suppressing effects in numerous cell types. We have shown that anandamide decreases cholangiocarcinoma growth in vitro. Therefore, we determined the effects of anandamide on cholangiocarcinoma tumor growth in vivo using a xenograft model and evaluated the effects of anandamide on the noncanonical Wnt signaling pathways. Chronic administration of anandamide decreased tumor growth and was associated with increased Wnt 5a expression in vitro and in vivo. Treatment of cholangiocarcinoma cells with recombinant Wnt 5a decreased cell proliferation in vitro. Neither anandamide nor Wnt 5a affected intracellular calcium release, but both increased the JNK phosphorylation. Stable knockdown of Wnt 5a or Ror2 expression in cholangiocarcinoma cells abolished the effects of anandamide on cell proliferation and JNK activation. Modulation of the endocannabinoid system may be important in cholangiocarcinoma treatment. The antiproliferative actions of the noncanonical Wnt signaling pathway warrants further investigation to dissect the mechanism by which this may occur.

scholarly journals Hsa_circ_0026416 promotes proliferation and migration in colorectal cancer via miR-346/NFIB axis

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Yahang Liang ◽  
Jingbo Shi ◽  
Qingsi He ◽  
Guorui Sun ◽  
Lei Gao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Molecular Mechanisms ◽  
Xenograft Model ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Potential Biomarker ◽  
Mouse Xenograft Model

Abstract Background Colorectal cancer (CRC) is one of the most common cancers worldwide. Circular RNAs (circRNAs), a novel class of non-coding RNAs, have been confirmed to be key regulators of many diseases. With many scholars devoted to studying the biological function and mechanism of circRNAs, their mysterious veil is gradually being revealed. In our research, we explored a new circRNA, hsa_circ_0026416, which was identified as upregulated in CRC with the largest fold change (logFC = 3.70) of the evaluated circRNAs via analysing expression profiling data by high throughput sequencing of members of the GEO dataset (GSE77661) to explore the molecular mechanisms of CRC. Methods qRT-PCR and western blot analysis were utilized to assess the expression of hsa_circ_0026416, miR-346 and Nuclear Factor I/B (NFIB). CCK-8 and transwell assays were utilized to examine cell proliferation, migration and invasion in vitro, respectively. A luciferase reporter assay was used to verify the combination of hsa_circ_0026416, miR-346 and NFIB. A nude mouse xenograft model was also utilized to determine the role of hsa_circ_0026416 in CRC cell growth in vivo. Results Hsa_circ_0026416 was markedly upregulated in CRC patient tissues and plasma and was a poor prognosis in CRC patients. In addition, the area under the curve (AUC) of hsa_circ_0026416 (0.767) was greater than the AUC of CEA (0.670), CA19-9 (0.592) and CA72-4 (0.575). Functionally, hsa_circ_0026416 promotes cell proliferation, migration and invasion both in vitro and in vivo. Mechanistically, hsa_circ_0026416 may function as a ceRNA via competitively absorbing miR-346 to upregulate the expression of NFIB. Conclusions In summary, our findings demonstrate that hsa_circ_0026416 is an oncogene in CRC. Hsa_circ_0026416 promotes the progression of CRC via the miR-346/NFIB axis and may represent a potential biomarker for diagnosis and therapy in CRC.

scholarly journals CRISPR/Cas9-mediated knockout of NSD1 suppresses the hepatocellular carcinoma development via the NSD1/H3/Wnt10b signaling pathway

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Shuhua Zhang ◽  
Fan Zhang ◽  
Qing Chen ◽  
Chidan Wan ◽  
Jun Xiong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Malignant Tumor ◽  
Quantitative Polymerase Chain Reaction ◽  
Xenograft Model ◽  
Migration And Invasion ◽  
Mouse Xenograft Model ◽  
Hcc Cells

Abstract Background The NSD family of histone lysine methyltransferases have emerged as important biomarkers that participate in a variety of malignancies. Recent evidence has indicated that somatic dysregulation of the nuclear receptor binding SET domain-containing protein 1 (NSD1) is associated with the tumorigenesis in HCC, suggesting that NSD1 may serve as a prognostic target for this malignant tumor. However, its mechanism in human hepatocellular carcinoma (HCC), the major primary malignant tumor in the human liver, remains unclear. Hence, we investigated how NSD1 regulated HCC progression via regulation of the Wnt/β-catenin signaling pathway. Methods Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis was performed to identify the expression of NSD1 in HCC cells and clinically obtained tissues. The relationship between NSD1 expression and prognosis was analyzed by Kaplan-Meier survival curve. Further, a NSD1 knockout cell line was constructed by CRISPR/Cas9 genomic editing system, which was investigated in a battery of assays such as HCC cell proliferation, migration and invasion, followed by the investigation into NSD1 regulation on histone H3, Wnt10b and Wnt/β-catenin signaling pathway via ChIP. Finally, a nude mouse xenograft model was conducted in order to assess tumorigenesis affected by NSD1 knockout in vivo. Results NSD1 was overexpressed in HCC tissues and cell lines in association with poor prognosis. Knockout of NSD1 inhibited the proliferation, migration and invasion abilities of HCC cells. CRISPR/Cas9-mediated knockout of NSD1 promoted methylation of H3K27me3 and reduced methylation of H3K36me2, which inhibited Wnt10b expression. The results thereby indicated an inactivation of the Wnt/β-catenin signaling pathway suppressed cell proliferation, migration and invasion in HCC. Moreover, these in vitro findings were reproduced in vivo on tumor xenograft in nude mice. Conclusion In conclusion, the study provides evidence that CRISPR/Cas9-mediated NSD1 knockout suppresses HCC cell proliferation and migration via the NSD1/H3/Wnt10b signaling pathway, suggesting that NSD1, H3 and Wnt10b may serve as potential targets for HCC.

scholarly journals A fusion of CD63–BCAR4 identified in lung adenocarcinoma promotes tumorigenicity and metastasis

2020 ◽  
Vol 124 (1) ◽  
pp. 290-298
Author(s):  
Kieun Bae ◽  
Jin Hee Kim ◽  
Hyojik Jung ◽  
Sun-Young Kong ◽  
Yun-Hee Kim ◽  
...  
Keyword(s):  
Cell Migration ◽  
Lung Adenocarcinoma ◽  
Fusion Gene ◽  
Animal Experiments ◽  
Xenograft Model ◽  
Fusion Transcript ◽  
Sequencing Data ◽  
Mouse Xenograft Model

Abstract Background Recently, fusion variants of the breast cancer anti-oestrogen-resistance 4 (BCAR4) gene were recurrently discovered in lung adenocarcinoma from the genome-wide studies. However, the functional characterisation of BCAR4 fusion has not been investigated. Methods Based on the analysis of RNA-sequencing data, we identified a fusion transcript of CD63–BCAR4 in a Korean patient with lung adenocarcinoma who did not harbour any known activating mutations in EGFR and KRAS genes. To investigate the oncogenic effect of CD63–BCAR4, in vitro and in vivo animal experiments were performed. Results In vitro experiments showed strongly enhanced cell migration and proliferation by the exogenous expression of CD63–BCAR4 protein in bronchial epithelial cells. Cell migration was notably reduced after knockdown of BCAR4 fusion by small-interfering RNA. The tumorigenic and metastatic capability of the CD63–BCAR4 fusion was confirmed by using the mouse xenograft model. Fusion-overexpressed cells result in metastasis to the liver and lung as well as the primary tumours after subcutaneous injection into mice. Cyclin D1, MMP1, Slug and mesenchymal markers were significantly increased after CD63–BCAR4 overexpression in the in vitro and in vivo experiments. Conclusions Taken together, our results suggest a newly identified fusion gene, CD63–BCAR4 as a potential novel oncogene in lung adenocarcinoma.

scholarly journals MiR-129-5p Inhibits Proliferation and Invasion of Chondrosarcoma Cells by Regulating SOX4/Wnt/β-Catenin Signaling Pathway

2017 ◽  
Vol 42 (1) ◽  
pp. 242-253 ◽  
Author(s):  
Peng Zhang ◽  
Jifeng Li ◽  
Yuze Song ◽  
Xiao Wang 
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Xenograft Model ◽  
Tumor Xenograft ◽  
Luciferase Assay ◽  
Tissue Samples ◽  
Proliferation And Apoptosis ◽  
Colony Forming Assay

Background/Aims: Recently, microRNAs (miRNA) have been identified as novel regulators in Chondrosarcoma (CHS). This study was aimed to identify the roles of miR-129-5p-5p in regulation of SOX4 and Wnt/β-catenin signaling pathway, as well as cell proliferation and apoptosis in chondrosarcomas. Materials and Methods: Tissue samples were obtained from chondrosarcoma patients. Immunohistochemistry, real-time quantitative RT-PCR (RT-qPCR) and western blot analysis were performed to detect the expressions of miR-129-5p and SOX4. Luciferase assay was conducted to confirm that miR-129-5p directly targeted SOX4 mRNA. Manipulations of miR-129-5p and SOX4 expression were achieved through cell transfection. Cell proliferation, migration and apoptosis were evaluated by CCK-8 assay, colony forming assay, wound healing assay and flow cytometry in vitro. For in vivo experiment, the tumor xenograft model was established to evaluate the effects of miR-129-5p and SOX4 on chondrosarcomas. Results: The expression of miR-129-5p was significantly down-regulated in chondrosarcoma tissues as well as cells in comparison with normal ones, while SOX4 was over-activated. Further studies suggested that miR-129-5p suppressed cell proliferation, migration and promoted apoptosis by inhibiting SOX4 and Wnt/β-catenin pathway. Conclusion: MiR-129-5p inhibits the Wnt/β-catenin signaling pathway by targeting SOX4 and further suppresses cell proliferation, migration and promotes apoptosis in chondrosarcomas.

scholarly journals Oncogenic Effect of the Novel Fusion Gene VAPA-Rab31 in Lung Adenocarcinoma

2019 ◽  
Vol 20 (9) ◽  
pp. 2309 ◽  
Author(s):  
Daseul Yoon ◽  
Kieun Bae ◽  
Jin-Hee Kim ◽  
Yang-Kyu Choi ◽  
Kyong-Ah Yoon
Keyword(s):  
Lung Adenocarcinoma ◽  
Fusion Gene ◽  
Protein A ◽  
Xenograft Model ◽  
Terminal Region ◽  
The Novel ◽  
Sequencing Data ◽  
Mouse Xenograft Model

Fusion genes have been identified as oncogenes in several solid tumors including lung, colorectal, and stomach cancers. Here, we characterized the fusion gene, VAPA-Rab31, discovered from RNA-sequencing data of a patient with lung adenocarcinoma who did not harbor activating mutations in EGFR, KRAS and ALK. This fusion gene encodes a protein comprising the N-terminal region of vesicle-associated membrane protein (VAMP)-associated protein A (VAPA) fused to the C-terminal region of Ras-related protein 31 (Rab31). Exogenous expression of VAPA-Rab31 in immortalized normal bronchial epithelial cells demonstrated the potential transforming effects of this fusion gene, including increased colony formation and cell proliferation in vitro. Also, enhanced tumorigenicity upon VAPA-Rab31 was confirmed in vivo using a mouse xenograft model. Metastatic tumors were also detected in the liver and lungs of xenografted mice. Overexpression of VAPA-Rab31 upregulated anti-apoptotic protein Bcl-2 and phosphorylated CREB both in cells and xenograft tumors. Reduced apoptosis and increased phosphorylation of CREB and Erk were observed in VAPA-Rab31-overexpressing cells after bortezomib treatment. Elevated Bcl-2 level via activated CREB contributed to the resistance to the bortezomib-induced apoptosis. Our data suggest the oncogenic function of the novel fusion gene VAPA-Rab31 via upregulated Bcl-2 and activated CREB in lung cancer.

scholarly journals HEATR1 promotes proliferation in gastric cancer in vitro and in vivo

2020 ◽  
Vol 52 (9) ◽  
pp. 1030-1039
Author(s):  
Jun Zhao ◽  
Yiping Zhu ◽  
Qingsheng Fu ◽  
Yimei Zhu ◽  
Guohai Zhao
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Xenograft Model ◽  
The Cancer Genome Atlas ◽  
Antibody Array ◽  
Mouse Xenograft Model ◽  
In Vivo Growth

Abstract HEAT repeat-containing protein 1 (HEATR1) is related to the progression of several cancers. However, the role of HEATR1 in gastric cancer (GC) remains unknown. In the present study, we aimed to detect the expression of HEATR1 in GC and identify its role. The expressions of HEATR1 in GC tissues were analyzed using The Cancer Genome Atlas database and by western blot analysis and immunohistochemistry. Furthermore, the HEATR1 expressions in GC cell lines MGC-803 and AGS were knocked down by using lentivirus-mediated HEATR1 shRNA. Cell proliferation and apoptosis were detected by CCK-8 and Caspase-Glo® 3/7 assays, respectively. PathScan® Signaling Antibody Array kit and Kyoto Encyclopedia of Genes and Genomes enrichment were used to study the pathways related to HEATR1. The influence of HEATR1 shRNA on the in vivo growth of GC cells was assessed by establishing a nude mouse xenograft model and conducting bioluminescence imaging. Our results showed that HEATR1 was highly expressed in GC tissues. Higher expression of HEATR1 is related to cancer progression and metastasis. Knocking down HEATR1 significantly suppressed the cell proliferation and colony formation and promoted cell apoptosis. The expression levels of phosphorylated p53, p38 MAPK, Chk2, and IKBa in shHEATR1-transfected MGC-803 cells exceeded those in shCtrl-transfected cells. HEATR1 shRNA treatment also significantly inhibited tumor growth in the mouse model. This study suggested that HEATR1 may be an oncogene and a target for GC therapy.

scholarly journals Overexpression of FBXO17 Promotes the Proliferation, Migration and Invasion of Glioma Cells Through the Akt/GSK-3β/Snail Pathway

2021 ◽  
Vol 30 ◽  
pp. 096368972110073
Author(s):  
Ning Wang ◽  
Qian Song ◽  
Hai Yu ◽  
Gang Bao
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Glioma Cells ◽  
Migration And Invasion ◽  
Vimentin Expression ◽  
Protein Levels ◽  
Cellular Behaviors ◽  
Gsk 3Β

FBXO17 is a newly studied F-box protein associated with high-grade glioma. However, its exact role in glioma remains unclear. In the present study, we aimed to investigate the role of FBXO17 in glioma both in vitro and in vivo and explore the underlying mechanism. Our results showed that FBXO17 mRNA and protein levels were upregulated in glioma cells including U87, U251, SHG44, and U-118-MG cells as compared to the HA1800 cells. Downregulation of FBXO17 significantly suppressed the cellular behaviors of glioma cells including cell proliferation, migration, and invasion. In addition, FBXO17 knockdown induced E-cadherin expression and inhibited N-cadherin and vimentin expression at mRNA and protein levels in glioma cells. In contrast, overexpression of FBXO17 promoted cell proliferation, migration, invasion and EMT process. Furthermore, FBXO17 regulated the Akt/GSK-3β/snail signaling pathway in glioma cells with significant changes in the expression levels of p-Akt, p-GSK-3β and snail. Additionally, inhibition of Akt by LY294002 reversed the effects of FBXO17 overexpression on cellular behaviors of glioma cells. Finally, in vivo mouse xenograft assay proved that downregulation of FBXO17 suppresses the tumorigenesis of glioma. In conclusion, these findings demonstrated that FBXO17 acted as a promotor of glioma development via modulating Akt/GSK-3β/snail signaling pathway.

scholarly journals NCAPG promotes the progression of lung adenocarcinoma via the TGF-β signaling pathway

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yun Wu ◽  
Ying Lin ◽  
Junfan Pan ◽  
Xunwei Tu ◽  
Yiquan Xu ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Cox Regression ◽  
Case Fatality ◽  
Immunohistochemical Analysis ◽  
Mesenchymal Transition

Abstract Background Lung cancer has the highest case fatality rate among cancers because of uncontrolled proliferation and early metastasis of cancer cells in the lung tissue. This study aimed to clarify the role of the non-SMC condensin I complex, subunit G (NCAPG) in lung adenocarcinoma (LUAD), explore the mechanisms of its progression, and lay the foundation for the search for new biological markers. Methods We analyzed overlapping differentially expressed genes (DEGs) from three datasets; a protein–protein interaction (PPI) network was subsequently constructed and analyzed using Cytoscape. We then selected NCAPG for validation because of its poor prognosis and because it has not been sufficiently studied in the context of LUAD. Immunohistochemical analysis was used to detect the expression of NCAPG in LUAD tissues, and the relationships between NCAPG and clinical parameters were analyzed. In vitro and in vivo experiments were conducted to verify the role of NCAPG in LUAD. Finally, we studied the specific mechanism of action of NCAPG in LUAD. Results Through comprehensive analysis of the GSE43458, GSE75037, and The Cancer Genome Atlas databases, we identified 517 overlapping DEGs. Among them, NCAPG was identified as a hub gene. Immunohistochemical analysis revealed that NCAPG was strongly associated with the clinical stage, M-classification, and N-classification. Univariate and multivariate Cox regression analyses indicated that NCAPG was a prognostic risk factor for LUAD, while the in vitro experiments showed that NCAPG overexpression promoted proliferation, migration, invasion, and epithelial-mesenchymal transition. Furthermore, knockdown of NCAPG inhibited LUAD progression, both in vitro and in vivo. Mechanistically, NCAPG overexpression increased p-Smad2 and p-Smad3 expressions in the transforming growth factor β (TGF-β) signaling pathway. Additionally, rescue experiments indicated that TGF-β signaling pathway inhibitors could restore the effect of NCAPG overexpression in LUAD cells. Conclusions NCAPG may promote proliferation and migration via the TGF-β signaling pathway in LUAD.

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