scholarly journals Hypoxia-induced PLOD1 overexpression contributes to the malignant phenotype of glioblastoma via NF-κB signaling

Oncogene ◽  
2021 ◽  
Author(s):  
Zhenlin Wang ◽  
Yuping Shi ◽  
Chenting Ying ◽  
Yang Jiang ◽  
Jiangfeng Hu
Keyword(s):  
Bioinformatics Analysis ◽  
Malignant Tumors ◽  
Tumor Xenograft ◽  
Clinical Samples ◽  
Treatment Target ◽  
Tumor Tissues ◽  
Tumor Viability ◽  
Lysyl Hydroxylase 1

AbstractProcollagen lysyl hydroxylase 1 (PLOD1) is highly expressed in malignant tumors such as esophageal squamous cell carcinoma, gastric cancer, and colorectal cancer. Bioinformatics analysis revealed that PLOD1 is associated with the progression of GBM, particularly the most malignant mesenchymal subtype (MES). Moreover, in the TCGA and CGGA datasets, the mean survival time of patients with high PLOD1 expression was significantly shorter than that of patients with low expression. The clinical samples confirmed this result. Therefore, we aimed to investigate the effect of PLOD1 on the development of mesenchymal GBM in vitro and in vivo and its possible mechanisms. Molecular experiments were conducted on the patient-derived glioma stem cells and found that PLOD1 expressed higher in tumor tissues and cancer cell lines of patients with GBM, especially in the MES. PLOD1 also enhanced tumor viability, proliferation, migration, and promoted MES transition while inhibited apoptosis. Tumor xenograft results also indicated that PLOD1 overexpression significantly promotes malignant behavior of tumors. Mechanistically, bioinformatics analysis further revealed that PLOD1 expression was closely associated with the NF-κB signaling pathway. Besides, we also found that hypoxic environments also enhanced the tumor-promoting effects of PLOD1. In conclusion, overexpression of PLOD1 may be an important factor in the enhanced invasiveness and MES transition of GBM. Thus, PLOD1 is a potential treatment target for mesenchymal GBM or even all GBM.

scholarly journals CDK5RAP3 inhibits angiogenesis in gastric neuroendocrine carcinoma by modulating AKT/HIF-1α/VEGFA signaling

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Jian-Xian Lin ◽  
Xiong-Feng Weng ◽  
Xin-Sheng Xie ◽  
Ning-Zi Lian ◽  
Sheng-Liang Qiu ◽  
...  
Keyword(s):  
Neuroendocrine Carcinoma ◽  
Poor Prognosis ◽  
Malignant Tumors ◽  
Umbilical Vein ◽  
Tube Formation ◽  
Tumor Xenograft ◽  
Biological Behavior ◽  
Tumor Tissues ◽  
Gastric Neuroendocrine Carcinoma

Abstract Background Angiogenesis plays critical roles in the progression and metastasis of malignant tumors. Gastric neuroendocrine carcinoma is an uncommon stomach cancer that is rich in blood vessels and exhibits highly malignant biological behavior with a poor prognosis. The role of CDK5RAP3 in GNEC has not been reported to date. Methods Immunohistochemistry was used to assess the expression of CDK5RAP3 in GNEC tissues and adjacent non-tumor tissues. Cell lines with stable overexpression or knockdown of CDK5RAP3 were constructed using lentiviral transfection. Wound-healing assays, invasion and metastasis assays, tube formation assays, and tumor xenograft transplantation assays were performed to evaluate the effect of CDK5RAP3 on GNEC angiogenesis in vitro and in vivo. Real-time PCR, ELISA, western blot analysis, and confocal-immunofluorescence staining were used to explore the molecular mechanism of CDK5RAP3′s effect on angiogenesis. Results Compared with their respective adjacent non-tumor tissues, protein levels of CDK5RAP3 were significantly decreased in GNEC tissues. Furthermore, low expression of CDK5RAP3 was correlated with more advanced TNM stage, increased tumor microvessel density, and poor prognosis. Functionally, we found that GNEC cells with CDK5RAP3 knockdown promoted human umbilical vein endothelial cells migration and tube formation via activation of AKT/HIF-1α/VEGFA signaling, resulting in increased levels of VEGFA in GNEC cell supernatant. In addition, CDK5RAP3 overexpression in GNEC cells caused the opposing effect. Consistent with these results, nude mouse tumorigenicity assays showed that CDK5RAP3 expression downregulated angiogenesis in vivo. Lastly, patients with low CDK5RAP3 expression and high VEGFA expression exhibited the worst prognosis. Conclusions This study demonstrated that CDK5RAP3 inhibits angiogenesis by downregulating AKT/HIF-1α/VEGFA signaling in GNEC and improves patient prognosis, suggesting that CDK5RAP3 could be a potential therapeutic target for GNEC.

scholarly journals LncRNA-URHC Functions as ceRNA to Regulate DNAJB9 Expression by Competitively Binding to miR-5007-3p in Hepatocellular Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Kunwei Niu ◽  
Shibin Qu ◽  
Xuan Zhang ◽  
Jimin Dai ◽  
Jianlin Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Bioinformatics Analysis ◽  
Biological Effects ◽  
Tumor Xenograft ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Underlying Mechanisms ◽  
Hcc Cells

Background. Hepatocellular carcinoma (HCC) is often diagnosed at a late stage, when the prognosis is poor. The regulation of long noncoding RNAs (lncRNAs) plays a crucial role in HCC. However, the precise regulatory mechanisms of lncRNA signaling in HCC remain largely unknown. Our study aims to investigate the underlying mechanisms of lncRNA (upregulated in hepatocellular carcinoma) URHC in HCC. Objective. To study the in vivo and in vitro localization and biological effects of URHC on liver cancer cells. Through bioinformatics analysis, dual-luciferase reporter gene analysis and rescue experiments revealed the possible mechanism of URHC. Methods. RT-qPCR, fluorescence in situ hybridization (FISH) staining, EdU, colony formation, and tumor xenograft experiments were used to identify localized and biological effects of URHC on HCC cells in vitro and in vivo. The bioinformatics analysis, dual-luciferase reporter assay, and rescue experiments revealed the potential mechanism of URHC. Results. URHC silencing may inhibit the HCC cells’ proliferation in vitro and in vivo. We found that URHC was mainly localized in the cytoplasm. The expression of miR-5007-3p was negatively regulated by URHC. And miR-5007-3p could reverse the effect of URHC in HCC cells. The expression of DNAJB9 was negatively regulated by miR-5007-3p but positively regulated by URHC. These suggestive of lncRNA-URHC positively regulated the level of DNAJB9 by sponging miR-5007-3p. Conclusion. Together, our study elucidated the role of URHC as a miRNA sponge in HCC and shed new light on lncRNA-directed diagnostics and therapeutics in HCC.

scholarly journals Hypoxia-Induced ROS Promotes Mitochondrial Fission and Cisplatin Chemosensitivity via HIF-1α/Mff Regulation

2020 ◽  
Author(s):  
Kun Wu ◽  
Yuan-yuan Mao ◽  
Qi Chen ◽  
Bolin Zhang ◽  
Sheng Zhang ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
Mitochondrial Dynamics ◽  
Dynamic Balance ◽  
Mitochondrial Fission ◽  
Hypoxia Inducible Factor ◽  
Hypoxic Condition ◽  
Clinical Samples ◽  
Hypoxic Conditions

Chemotherapy treatment based on Cisplatin (CDDP) is established as the drug of choice for head and neck squamous cell carcinoma (HNSCC). Malignant tumors respond to microenvironment alteration through a dynamic balance of mitochondrial fission and fusion. HNSCC is known to have hypoxic conditions, yet the effects and underlying mechanisms of hypoxia on chemosensitivity and mitochondrial dynamics remain unclear. We found that hypoxia promoted mitochondrial fission and CDDP sensitivity in HNSCC cells. Importantly, Mff was shown to be correlated with chemosensitivity in clinical samples of HNSCC that underwent a hypoxic condition. Hypoxia-inducible factor 1 α-subunit (HIF-1α) dramatically increased Mff transcriptional expression and directly bound to Mff. Hypoxia enhanced the release of reactive oxygen species (ROS) and upregulated the expression of Mff via HIF-1α in HNSCC cells. ROS depletion in HNSCC cells attenuated HIF-1α, Mff expression, and mitochondrial fission. Moreover, a knockdown of Mff suppressed hypoxia-induced mitochondrial fission and decreased CDDP chemosensitivity in vivo and in vitro. Our findings revealed that the hypoxia-induced release of ROS promoted mitochondrial fission and CDDP chemosensitivity via the regulation of HIF-1α/Mff in HNSCC cells, indicating that Mff may serve as a new biomarker to predict neoadjuvant chemosensitivity in HNSCC patients

scholarly journals LncRNA KASRT Serves as a Potential Treatment Target by Regulating SRSF1-Related KLF6 Alternative Splicing and the P21/CCND1 Pathway in Osteosarcoma: An In Vitro and In Vivo Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Kai Chen ◽  
Cheng Li ◽  
Shuai Huang ◽  
Yu Chen ◽  
Xiaodong Zhu
Keyword(s):  
Alternative Splicing ◽  
Control Cell ◽  
Tumor Xenograft ◽  
Osteosarcoma Cell ◽  
Potential Treatment ◽  
Treatment Target ◽  
Apoptotic Marker ◽  
Marker Expression

PurposeLong non-coding RNA KLF6 alternative splicing regulating transcript (lnc-KASRT) locates within the intronic region of SRSF1, possessing the potential to regulate KLF6 alternative splicing to promote carcinogenicity. Then, the current in vitro and in vivo study aimed to investigate the effect of lnc-KASRT on regulating tumor malignant behaviors, and the implication of its interaction with KLF6 alternative splicing in osteosarcoma.MethodsLnc-KASRT overexpression or knockdown plasmid was transfected into U-2OS and Saos-2 cells. Then, KLF6-SV1 knockdown plasmid with or without lnc-KASRT overexpression plasmid was transfected into these cells for compensative experiments. In vivo, lnc-KASRT overexpression or knockdown Saos-2 cells were injected in mice for tumor xenograft construction.ResultsLnc-KASRT expression was increased in most osteosarcoma cell lines compared to control cell line. Lnc-KASRT overexpression promoted cell viability, mobility, and anti-apoptotic marker expression, while reducing apoptosis rate and pro-apoptotic marker expression; meanwhile, it regulated SRSF1, KLF6 alternative splicing (increased KLF6-splice variant 1 (KLF6-SV1), decreased KLF6-wild type (KLF6-WT)), and followed P21/CCND1 pathway in U-2OS/Saos-2 cells. The lnc-KASRT knockdown exhibited opposite trends. Subsequent compensative experiments disclosed that KLF6-SV1 knockdown attenuated most of the tumor-promoting effects of lnc-KASRT overexpression in U-2OS/Saos-2 cells. In vivo experiments further validated that lnc-KASRT enhanced tumor growth and reduced tumor apoptosis; meanwhile, it also increased tumor KLF6-SV1, MMP-1, and MMP-9 expressions but decreased tumor SRSF1 and KLF6-WT expressions in xenograft mice.ConclusionLnc-KASRT serves as a potential treatment target via regulating SRSF1-related KLF6 alternative splicing and following P21/CCND1 pathway in osteosarcoma.

Cholesterol Sensor SCAP Contributes to Sorafenib Resistance by Regulating Autophagy in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Danyang Li ◽  
Yingcheng Yao ◽  
Yuhan Rao ◽  
Xinyu Huang ◽  
Li Wei ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Malignant Tumors ◽  
Acquired Resistance ◽  
Clinical Samples ◽  
Significant Finding ◽  
Sorafenib Treatment ◽  
Associated Risk Factors

Abstract Background: Hepatocellular carcinoma (HCC) is one of the most malignant tumors and the fourth leading cause of cancer-related death worldwide. Sorafenib is currently acknowledged as a standard therapy for advanced HCC. However, acquired resistance substantially limits the clinical efficacy of sorafenib. Therefore, further investigations of the associated risk factors are highly warranted.Methods: We analysed a group of 78 HCC patients who received sorafenib treatment after liver resection surgery. The expression of SCAP and its correlation with sorafenib resistance in HCC clinical samples were determined by immunohistochemical analyses. Overexpression and knockdown approaches in vitro were used to characterize the functional roles of SCAP in regulating sorafenib resistance. The effects of SCAP inhibition in HCC cell lines were analysed in proliferation, apoptosis, and colony formation assays. Autophagic regulation by SCAP was assessed by immunoblotting, immunofluorescence and immunoprecipitation assays. The combinatorial effect of a SCAP inhibitor and sorafenib was tested using nude mice.Results: Hypercholesterolemia was associated with sorafenib resistance in HCC treatment. The degree of sorafenib resistance was correlated with the expression of the cholesterol sensor SCAP and consequent deposition of cholesterol. SCAP is overexpressed in HCC tissues and hepatocellular carcinoma cell lines with sorafenib resistance, while SCAP inhibition could improve sorafenib sensitivity in sorafenib-resistant HCC cells. Furthermore, we found that SCAP-mediated sorafenib resistance was related to decreased autophagy, which was connected to decreased AMPK activity. A clinically significant finding was that lycorine, a specific SCAP inhibitor, could reverse acquired resistance to sorafenib in vitro and in vivo.Conclusions: SCAP contributes to sorafenib resistance through AMPK-mediated autophagic regulation. The combination of sorafenib and SCAP targeted therapy provides a novel personalized treatment to enhance sensitivity in sorafenib-resistant HCC.

Long noncoding RNA Linc01296 promotes hepatocellular carcinoma development through regulation of the miR-26a/PTEN axis

2020 ◽  
Vol 401 (3) ◽  
pp. 407-416 ◽  
Author(s):  
Libin Zhang ◽  
Jing Hu ◽  
Menghui Hao ◽  
Liang Bu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Malignant Tumors ◽  
Cell Counting ◽  
Tumor Xenograft ◽  
Migration And Invasion

AbstractLong noncoding RNA 01296 (Lnc01296) is dysregulated in malignant tumors. However, the detailed effect of Linc01296 on hepatocellular carcinoma (HCC) remains largely unknown. In this study, we identified the biological role of Linc01296 in HCC. The levels of Linc01296 in HCC tissues and a panel of cell lines were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). The effects of Linc01296 on HCC progression were explored using a Cell Counting Kit-8 (CCK-8), flow cytometry, migration and Transwell invasion assays. The interactions among Linc01296, miR-26a and PTEN were determined using luciferase, RNA immunoprecipitation (RIP) and Western blot assays. Tumor xenograft models were utilized to confirm the in vivo functional roles of Linc01296 in HCC development. Linc01296 expression was increased in both HCC tissue samples and cell lines. Knockdown of Linc01296 suppressed HCC cell processes, such as proliferation, migration and invasion, and enhanced apoptosis in vitro; these effects were reversed by a miR-26a mimic or PTEN overexpression. Furthermore, knockdown of Linc01296 suppressed HCC growth in vivo. These findings indicated that Linc01296 is involved in HCC progression via regulating miR-26a/PTEN.

scholarly journals LINC00667 Sponges miR-4319 to Promote the Development of Nasopharyngeal Carcinoma by Increasing FOXQ1 Expression

2021 ◽  
Vol 10 ◽  
Author(s):  
Bing Liao ◽  
Yun Yi ◽  
Lei Zeng ◽  
Zhi Wang ◽  
Xinhua Zhu ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Bioinformatics Analysis ◽  
Epithelial Mesenchymal Transition ◽  
Malignant Tumors ◽  
Mechanistic Study ◽  
Small Cell Lung ◽  
Mesenchymal Transition ◽  
Forkhead Box

Accumulating evidence has indicated that lncRNAs regulate various biological and pathological processes in diverse malignant tumors. The roles of LINC00667 in cancer development have been explored in glioma, hepatocellular carcinoma and non-small cell lung cancer, but not in nasopharyngeal carcinoma (NPC). In the present study, we characterize the role and molecular mechanism of LINC00667 in NPC progression. It was found that LINC00667 was overexpressed in NPC cells compared to normal cells. Silencing LINC00667 suppressed the proliferation, migration, invasion and epithelial mesenchymal transition (EMT) in NPC cells. In addition, bioinformatics analysis revealed that LINC00667 acted as a ceRNA to absorb miR-4319. Further investigations illustrated that miR-4319 had low expression in NPC cells and functioned as a tumor suppressor in the progression of NPC. Mechanistic study identified forkhead box Q1 (FOXQ1) as a functional target of miR-4319. The effect of LINC00667 in NPC development was mediated by the miR-4319/FOXQ1 axis. Analysis on tumorxenograft mouse model demonstrated that knockdown of LINC00667 repressed NPC tumor growth in vivo and confirmed the in vitro results. Our present study suggested that LINC00667 promoted the malignant phenotypes of NPC cells by competitively binding to miR-4319 to up-regulate FOXQ1 expression. Our results reveled that LINC00667 could be a diagnostic and therapeutic target for NPC patients.

scholarly journals A novel BRD4 inhibitor suppresses osteoclastogenesis and ovariectomized osteoporosis by blocking RANKL-mediated MAPK and NF-κB pathways

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Ying Liu ◽  
Wenjie Liu ◽  
Ziqiang Yu ◽  
Yan Zhang ◽  
Yinghua Li ◽  
...  
Keyword(s):  
Bone Loss ◽  
Osteoporosis Treatment ◽  
Inhibitory Effect ◽  
Specific Gene ◽  
Actin Ring ◽  
Treatment Target ◽  
Significant Inhibitory Effect ◽  
Promising Treatment

AbstractBromodomain-containing protein 4 (BRD4) has emerged as a promising treatment target for bone-related disorders. (+)-JQ1, a thienotriazolodiazepine compound, has been shown to inhibit pro-osteoclastic activity in a BRD4-dependent approach and impede bone loss caused by ovariectomy (OVX) in vivo. However, clinical trials of (+)-JQ1 are limited because of its poor druggability. In this study, we synthesized a new (+)-JQ1 derivative differing in structure and chirality. One such derivative, (+)-ND, exhibited higher solubility and excellent inhibitory activity against BRD4 compared with its analogue (+)-JQ1. Interestingly, (-)-JQ1 and (-)-ND exhibited low anti-proliferative activity and had no significant inhibitory effect on RANKL-induced osteoclastogenesis as compared with (+)-JQ1 and (+)-ND, suggesting the importance of chirality in the biological activity of compounds. Among these compounds, (+)-ND displayed the most prominent inhibitory effect on RANKL-induced osteoclastogenesis. Moreover, (+)-ND could inhibit osteoclast-specific gene expression, F‐actin ring generation, and bone resorption in vitro and prevent bone loss in OVX mice. Collectively, these findings indicated that (+)-ND represses RANKL‐stimulated osteoclastogenesis and averts OVX-triggered osteoporosis by suppressing MAPK and NF-κB signalling cascades, suggesting that it may be a prospective candidate for osteoporosis treatment.

scholarly journals Anticancer Activity of Triazolo-Thiadiazole Derivatives and Inhibition of AKT1 and AKT2 Activation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 493
Author(s):  
Dimitrios T. Trafalis ◽  
Sofia Sagredou ◽  
Panayiotis Dalezis ◽  
Maria Voura ◽  
Stella Fountoulaki ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Human Colon ◽  
Tumor Xenograft ◽  
Atp Binding Site ◽  
Anticancer Properties ◽  
Extensive Range ◽  
Dependent Inhibition ◽  
Ht 29

The fusion of 1,2,4-triazole and 1,3,4-thiadiazole rings results in a class of heterocycles compounds with an extensive range of pharmacological properties. A series of 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles was synthesized and tested for its enzyme inhibition potential and anticancer activity. The results show that 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles display potent anticancer properties in vitro against a panel of cancer cells and in vivo efficacy in HT-29 human colon tumor xenograft in CB17 severe combined immunodeficient (SCID) mice. Preliminary mechanistic studies revealed that KA25 and KA39 exhibit time- and concentration-dependent inhibition of Akt Ser-473 phosphorylation. Molecular modeling experiments indicated that 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles bind well to the ATP binding site in Akt1 and Akt2. The low acute toxicity combined with in vitro and in vivo anticancer activity render triazolo[3,4-b]thiadiazoles KA25, KA26, and KA39 promising cancer therapeutic agents.

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