scholarly journals TIFA Promotes CRC Cell Proliferation via RSK- and PRAS40- Dependent Manner

2021 ◽  
Author(s):  
Wenzhi Shen ◽  
Wenfei Du ◽  
Yanping Li ◽  
Yongming Huang ◽  
Xinyu Jiang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Ectopic Expression ◽  
Xenograft Model ◽  
Tissue Microarrays ◽  
Underlying Mechanism ◽  
Dependent Manner ◽  
Site Mutation ◽  
Fha Domain

Abstract Background: Previous studies have shown that TIFA (TNF receptor associated factor (TRAF)-interacting protein with a Forkhead-associated (FHA) domain) plays different roles in various tumor types. However, the function of TIFA in colorectal cancer (CRC) remains unclear. The goal of this study is to uncover the biological function and molecular mechanism of TIFA in CRC.Methods: Tissue microarrays were used to evaluate TIFA expression. Cancer cell proferation assays were performed in TIFA knockdown and overexpressing cells in vitro and in a xenograft model in vivo. Human phosphokinase array, immunoprecipitation assays were performed to explore the underlying mechanism.Results: We disclosed that the expression of TIFA was marked increased in CRC versus normal tissue, and positively correlated with CRC TNM stages. In agreement, we found that the CRC cell lines show increased TIFA expression levels versus normal control. The knockdown of TIFA inhibited cell proliferation but have no effects on cell apoptosis in vitro and in vivo. Moreover, the ectopic expression of TIFA enhanced cell proliferation ability in vitro and in vivo. In contrast, the expression of mutant TIFA (T9A, oligomerization site mutation; D6, TRAF6 binding site deletion) alternatively abolished TIFA mediated cell proliferation enhancement. Exploration of the underlying mechanism demonstrated that the protein synthesis associated kinase RSK and PRAS40 activation were all responsible for TIFA mediated CRC progression. Conclusions: The above results described a model of TIFA in mediating CRC progression. This may provide a promising target for CRC therapy.

scholarly journals Apigenin Inhibits Histamine-Induced Cervical Cancer Tumor Growth by Regulating Estrogen Receptor Expression

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1960 ◽  
Author(s):  
Erkang Zhang ◽  
Yani Zhang ◽  
Zhuoyan Fan ◽  
Lei Cheng ◽  
Shiwen Han ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Antioxidant Properties ◽  
Xenograft Model ◽  
Receptor Expression ◽  
Dependent Manner ◽  
Antitumor Effects

Apigenin is a natural flavone with anti-inflammatory and antioxidant properties and antitumor abilities against several types of cancers. Previous studies have found that the antitumor effects of apigenin may be due to its similar chemical structure to 17β-estradiol (E2), a main kind of estrogen in women. However, the precise mechanism underlying the antitumor effects of apigenin in cervical cancer remains unknown. On the other hand, there is increasing evidence that describes a histamine role in cancer cell proliferation. In this study, we examined whether apigenin can attenuate the effects of histamine on tumors by regulating the expression level of estrogen receptors (ERs) to inhibit cervical cancer growth. Our in vitro data indicates that apigenin inhibited cell proliferation in a dose-dependent manner in human cervical cancer cells (HeLa), while histamine shows the opposite effects. After that, the xenograft model was established to explore the antitumor effects of apigenin in vivo, the results show that apigenin inhibited cervical tumor growth by reversing the abnormal ER signal in tumor tissue which was caused by histamine. We also demonstrate that apigenin inhibited cell proliferation via suppressing the PI3K/Akt/mTOR signaling pathway. Collectively, our results suggest that apigenin may inhibit tumor growth through the ER-mediated PI3K/Akt/mTOR pathway and that it can also attenuate the effects of histamine on tumors.

scholarly journals Zuo Jin Wan, a Traditional Chinese Herbal Formula, Reverses P-gp-Mediated MDRIn VitroandIn Vivo

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Hua Sui ◽  
Xuan Liu ◽  
Bao-Hui Jin ◽  
Shu-Fang Pan ◽  
Li-Hong Zhou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Multidrug Resistance ◽  
Xenograft Model ◽  
Underlying Mechanism ◽  
Dependent Manner ◽  
Chemotherapeutic Drugs ◽  
Reversal Effect

Zuo Jin Wan (ZJW), a typical traditional Chinese medicine (TCM) formula, has been identified to have anticancer activity in recent studies. In this study, we determined the underlying mechanism of ZJW in the reversal effect of multidrug resistance on colorectal cancerin vitroandin vivo. Our results showed that ZJW significantly enhanced the sensitivity of chemotherapeutic drugs in HCT116/L-OHP, SGC7901/DDP, and Bel/Fu MDR cells. Moreover, combination of chemotherapy with ZJW could reverse the drug resistance of HCT116/L-OHP cells, increase the sensitivity of HCT116/L-OHP cells to L-OHP, DDP, 5-Fu, and MMCin vitro, and inhibit the tumor growth in the colorectal MDR cancer xenograft model. ICP-MS results showed that ZJW could increase the concentration of chemotherapeutic drugs in HCT116/L-OHP cells in a dose-dependent manner. Furthermore, we showed that ZJW could reverse drug resistance of colorectal cancer cells by decreasing P-gp levelin vitroandin vivo, which has been represented as one of the major mechanisms that contribute to the MDR phenotype. Our study has provided the first direct evidence that ZJW plays an important role in reversing multidrug resistance of human colorectal cancer and may be considered as a useful target for cancer therapy.

scholarly journals A Traditional Chinese Medicine Herb Mixture Qingjie Fuzheng Granules Inhibits Hepatocellular Carcinoma Cells Growth by Inducing Apoptosis

2018 ◽  
Vol 23 ◽  
pp. 2515690X1878963 ◽  
Author(s):  
Pingping Zhong ◽  
Hong Yang ◽  
Shan Lin ◽  
Jun Peng ◽  
Jiumao Lin
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Body Weight Gain ◽  
Xenograft Model ◽  
Annexin V ◽  
Nuclear Staining ◽  
Dependent Manner ◽  
Mouse Xenograft Model

In this study, hepatocellular carcinoma (HCC) mouse xenograft model, MTT assay, colony formation, nuclear staining, and Annexin-V/PI staining assays were used to evaluate the effect of Qingjie Fuzheng granules (QFG) on cell proliferation and apoptosis of HCC cell in vivo and in vitro. Furthermore, Western blotting was performed to detect the expression of Fas, FasL, Bcl-2, Bax, and the activation of caspase-3/-8/-9. The results showed that QFG reduced tumor weight ( P < .05) but had no effect on body weight gain in HCC mice in vivo. QFG significantly reduced HCC cell viability and attenuated cell proliferation in a dose-dependent manner ( P < .05). QFG increased the expression of Fas, FasL, and Bax ( P < .05). QFG downregulated the expression of Bcl-2 and promoted the activation of caspase-8, -9, and -3 ( P < .05). These results suggested that QFG possessed anticancer effects, and the mechanisms of action may involve the death receptor pathway and mitochondrion-dependent pathway-mediated apoptosis.

scholarly journals Influence of icariin on inflammation, apoptosis, invasion, and tumor immunity in cervical cancer by reducing the TLR4/MyD88/NF-κB and Wnt/β-catenin pathways

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chunyang Li ◽  
Shuangqing Yang ◽  
Huaqing Ma ◽  
Mengjia Ruan ◽  
Luyan Fang ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Underlying Mechanism ◽  
Tissue Growth ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Siha Cells ◽  
Cervical Cancer Cells

Abstract Background Cervical cancer is a type of the most common gynecology tumor in women of the whole world. Accumulating data have shown that icariin (ICA), a natural compound, has anti-cancer activity in different cancers, including cervical cancer. The study aimed to reveal the antitumor effects and the possible underlying mechanism of ICA in U14 tumor-bearing mice and SiHa cells. Methods The antitumor effects of ICA were investigated in vivo and in vitro. The expression of TLR4/MyD88/NF-κB and Wnt/β-catenin signaling pathways were evaluated. Results We found that ICA significantly suppressed tumor tissue growth and SiHa cells viability in a dose-dependent manner. Also, ICA enhanced the anti-tumor humoral immunity in vivo. Moreover, ICA significantly improved the composition of the microbiota in mice models. Additionally, the results clarified that ICA significantly inhibited the migration, invasion capacity, and expression levels of TGF-β1, TNF-α, IL-6, IL-17A, IL-10 in SiHa cells. Meanwhile, ICA was revealed to promote the apoptosis of cervical cancer cells by down-regulating Ki67, survivin, Bcl-2, c-Myc, and up-regulating P16, P53, Bax levels in vivo and in vitro. For the part of mechanism exploration, we showed that ICA inhibits the inflammation, proliferation, migration, and invasion, as well as promotes apoptosis and immunity in cervical cancer through impairment of TLR4/MyD88/NF-κB and Wnt/β-catenin pathways. Conclusions Taken together, ICA could be a potential supplementary agent for cervical cancer treatment.

scholarly journals METTL14 promotes tumorigenesis by regulating lncRNA OIP5-AS1/miR-98/ADAMTS8 signaling in papillary thyroid cancer

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Xiaoping Zhang ◽  
Dan Li ◽  
Chengyou Jia ◽  
Haidong Cai ◽  
Zhongwei Lv ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Xenograft Model ◽  
Luciferase Reporter ◽  
Papillary Thyroid ◽  
Qrt Pcr ◽  
The Relationship

Abstract Background Papillary thyroid cancer (PTC) is the most common type of cancer of the endocrine system. Long noncoding RNAs (lncRNAs) are emerging as a novel class of gene expression regulators associated with tumorigenesis. Through preexisting databases available for differentially expressed lncRNAs in PTC, we uncovered that lncRNA OIP5-AS1 was significantly upregulated in PTC tissues. However, the function and the underlying mechanism of OIP5-AS1 in PTC are poorly understood. Methods Expression of lncRNA OIP5-AS1 and miR-98 in PTC tissue and cells were measured by quantitative real-time PCR (qRT-PCR). And expression of METTL14 and ADAMTS8 in PTC tissue and cells were measured by qRT-PCR and western blot. The biological functions of METTL14, OIP5-AS1, and ADAMTS8 were examined using MTT, colony formation, transwell, and wound healing assays in PTC cells. The relationship between METTL14 and OIP5-AS1 were evaluated using RNA immunoprecipitation (RIP) and RNA pull down assay. And the relationship between miR-98 and ADAMTS8 were examined by luciferase reporter assay. For in vivo experiments, a xenograft model was used to investigate the effects of OIP5-AS1 and ADAMTS8 in PTC. Results Functional validation revealed that OIP5-AS1 overexpression promotes PTC cell proliferation, migration/invasion in vitro and in vivo, while OIP5-AS1 knockdown shows an opposite effect. Mechanistically, OIP5-AS1 acts as a target of miR-98, which activates ADAMTS8. OIP5-AS1 promotes PTC cell progression through miR-98/ADAMTS8 and EGFR, MEK/ERK pathways. Furthermore, RIP and RNA pull down assays identified OIP5-AS1 as the downstream target of METTL14. Overexpression of METTL14 suppresses PTC cell proliferation and migration/invasion through inhibiting OIP5-AS1 expression and regulating EGFR, MEK/ERK pathways. Conclusions Collectively, our findings demonstrate that OIP5-AS1 is a METTL14-regulated lncRNA that plays an important role in PTC progression and offers new insights into the regulatory mechanisms underlying PTC development.

scholarly journals RASSF1A inhibits PDGFB-driven malignant phenotypes of nasopharyngeal carcinoma cells in a YAP1-dependent manner

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Ying-Ying Liang ◽  
Xu-Bin Deng ◽  
Xian-Tao Lin ◽  
Li-Li Jiang ◽  
Xiao-Ting Huang ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Underlying Mechanism ◽  
Carcinoma Cells ◽  
Dependent Manner ◽  
Transcriptional Coactivator ◽  
Actin Remodeling ◽  
Aggressive Tumor ◽  
Subunit B

Abstract Nasopharyngeal carcinoma (NPC) is a highly aggressive tumor characterized by distant metastasis. Deletion or down-regulation of the tumor suppressor protein ras-association domain family protein1 isoform A (RASSF1A) has been confirmed to be a key event in NPC progression; however, little is known about the effects or underlying mechanism of RASSF1A on the malignant phenotype. In the present study, we observed that RASSF1A expression inhibited the malignant phenotypes of NPC cells. Stable silencing of RASSF1A in NPC cell lines induced self-renewal properties and tumorigenicity in vivo/in vitro and the acquisition of an invasive phenotype in vitro. Mechanistically, RASSF1A inactivated Yes-associated Protein 1 (YAP1), a transcriptional coactivator, through actin remodeling, which further contributed to Platelet Derived Growth Factor Subunit B (PDGFB) transcription inhibition. Treatment with ectopic PDGFB partially increased the malignancy of NPC cells with transient knockdown of YAP1. Collectively, these findings suggest that RASSF1A inhibits malignant phenotypes by repressing PDGFB expression in a YAP1-dependent manner. PDGFB may serve as a potential interest of therapeutic regulators in patients with metastatic NPC.

scholarly journals A MYBL2 complex for RRM2 transactivation and the synthetic effect of MYBL2 knockdown with WEE1 inhibition against colorectal cancer

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Qian Liu ◽  
Lijuan Guo ◽  
Hongyan Qi ◽  
Meng Lou ◽  
Rui Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Dna Synthesis ◽  
Ectopic Expression ◽  
Building Blocks ◽  
Small Subunit ◽  
S Phase ◽  
Clinical Samples ◽  
Dependent Manner

AbstractRibonucleotide reductase (RR) is a unique enzyme for the reduction of NDPs to dNDPs, the building blocks for DNA synthesis and thus essential for cell proliferation. Pan-cancer profiling studies showed that RRM2, the small subunit M2 of RR, is abnormally overexpressed in multiple types of cancers; however, the underlying regulatory mechanisms in cancers are still unclear. In this study, through searching in cancer-omics databases and immunohistochemistry validation with clinical samples, we showed that the expression of MYBL2, a key oncogenic transcriptional factor, was significantly upregulated correlatively with RRM2 in colorectal cancer (CRC). Ectopic expression and knockdown experiments indicated that MYBL2 was essential for CRC cell proliferation, DNA synthesis, and cell cycle progression in an RRM2-dependent manner. Mechanistically, MYBL2 directly bound to the promoter of RRM2 gene and promoted its transcription during S-phase together with TAF15 and MuvB components. Notably, knockdown of MYBL2 sensitized CRC cells to treatment with MK-1775, a clinical trial drug for inhibition of WEE1, which is involved in a degradation pathway of RRM2. Finally, mouse xenograft experiments showed that the combined suppression of MYBL2 and WEE1 synergistically inhibited CRC growth with a low systemic toxicity in vivo. Therefore, we propose a new regulatory mechanism for RRM2 transcription for CRC proliferation, in which MYBL2 functions by constituting a dynamic S-phase transcription complex following the G1/early S-phase E2Fs complex. Doubly targeting the transcription and degradation machines of RRM2 could produce a synthetic inhibitory effect on RRM2 level with a novel potential for CRC treatment.

MondoA Drives B-ALL Malignancy through Enhanced Adaptation to Metabolic Stress

Blood ◽  
2021 ◽  
Author(s):  
Alexandra Sipol ◽  
Erik Hameister ◽  
Busheng Xue ◽  
Julia Hofstetter ◽  
Maxim Barenboim ◽  
...  
Keyword(s):  
Stress Responses ◽  
Lymphoblastic Leukemia ◽  
Metabolic Stress ◽  
Tca Cycle ◽  
Underlying Mechanism ◽  
Patient Data ◽  
Data Sets ◽  
Dependent Manner

Cancer cells are in most instances characterized by rapid proliferation and uncontrolled cell division. Hence, they must adapt to proliferation-induced metabolic stress through intrinsic or acquired anti-metabolic stress responses to maintain homeostasis and survival. One mechanism to achieve this is to reprogram gene expression in a metabolism-dependent manner. MondoA (also known as MLXIP), a member of the MYC interactome, has been described as an example of such a metabolic sensor. However, the role of MondoA in malignancy is not fully understood and the underlying mechanism in metabolic responses remains elusive. By assessing patient data sets we found that MondoA overexpression is associated with a worse survival in pediatric common acute lymphoblastic leukemia (B-ALL). Using CRISPR/Cas9 and RNA interference approaches, we observed that MondoA depletion reduces transformational capacity of B-ALL cells in vitro and dramatically inhibits malignant potential in an in vivo mouse model. Interestingly, reduced expression of MondoA in patient data sets correlated with enrichment in metabolic pathways. The loss of MondoA correlated with increased tricarboxylic acid (TCA) cycle activity. Mechanistically, MondoA senses metabolic stress in B-ALL cells by restricting oxidative phosphorylation through reduced PDH activity. Glutamine starvation conditions greatly enhance this effect and highlight the inability to mitigate metabolic stress upon loss of MondoA in B-ALL. Our findings give a novel insight into the function of MondoA in pediatric B-ALL and support the notion that MondoA inhibition in this entity offers a therapeutic opportunity and should be further explored.

scholarly journals Methylprednisolone Protects SAP and Pancreatitis-Associated ALI in Mice by Inhibiting NLRP3 Inflammasome Through NF-κB

2020 ◽  
Author(s):  
Chuan-jiang Liu ◽  
Qiang Fu ◽  
Wenjing Zhou ◽  
Xu Zhang ◽  
Rui Chen ◽  
...  
Keyword(s):  
Lung Tissue ◽  
Nlrp3 Inflammasome ◽  
Antioxidant Properties ◽  
Underlying Mechanism ◽  
Peritoneal Macrophages ◽  
Dependent Manner ◽  
Expression Levels ◽  
Tnf Α

Abstract Background: Methylprednisolone (MP) is a synthetic corticosteroid with potent anti-inflammatory and antioxidant properties used as therapy for a variety of diseases. The underlying mechanism of MP to reduce acute pancreatitis still needs to be elucidated.Methods: Twenty-four male C57BL/6 mice (6-8 weeks) were used to establish SAP mouse model by administering an intraperitoneal injection of Cae and LPS. Amylase expression levels of serum and PLF were measured with an amylase assay kit. The concentrations of IL-1β and TNF-α in the serum and PLF were detected by ELISA. The level of pancreatic and lung tissue damage and inflammation was assessed by H&E staining and immunofluorescence staining. Western blot and qPCR were used to detect the expression levels of NLRP3, IL-1β and TNF-αin vivo and in vitro.Results: In this study, we found MP, used in the early phase of SAP, decreased the levels of IL-1β and TNF-α in serum and peritoneal lavage fluids (PLF), reduced the level of serum amylase and the expression of MPO in lung tissue, attenuated the pathological injury of the pancreas and lungs in a dose-dependent manner. The expression of NLRP3 and IL-1β in pancreas and lungs was down-regulated significantly depending on the MP concentration. In vitro, MP reduced the levels of IL-1β and TNF-α by down-regulating the expression of NLRP3, IL-1β and p-NF-κB in isolated peritoneal macrophages. Conclusion: MP can attenuate the injury of pancreas and lungs, and the inflammatory response in SAP mice by down-regulating the activation of NF-κB and the NLRP3 inflammasome.

scholarly journals Curcumol inhibits malignant biological behaviors and TMZ-resistance of glioma cells via reducing long noncoding RNA FoxD2-As1 promoted EZH2 activation

2021 ◽  
Author(s):  
Xuyang Lv ◽  
Jiangchuan Sun ◽  
Linfeng Hu ◽  
Ying Qian ◽  
Chunlei Fan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Noncoding Rna ◽  
Glioma Cell ◽  
Glioma Cells ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Self Renewal

Abstract Background: Although curcumol has been shown to possess antitumor effects in several cancers, its effects on glioma are largely unknown. Recently, lncRNAs have been reported to play an oncogenic role through epigenetic modifications. Therefore, here, we investigated whether curcumol inhibited glioma progression by reducing FOXD2-AS1-mediated enhancer of zeste homolog 2 (EZH2) activation.Methods: MTT, colony formation, flow cytometry, Transwell, and neurosphere formation assays were used to assess cell proliferation, cell cycle, apoptosis, the percentage of CD133+ cells, the migration and invasion abilities, and the self-renewal ability. qRT-PCR, western blotting, immunofluorescence, and immunohistochemical staining were used to detect mRNA and protein levels. Isobologram analysis and methylation-specific PCR were used to analyze the effects of curcumol on TMZ resistance in glioma cells. DNA pull-down and Chip assays were employed to explore the molecular mechanism underlying the functions of curcumol in glioma cells. Tumorigenicity was determined using a xenograft formation assay. Results: Curcumol inhibited the proliferation, metastasis, self-renewal ability, and TMZ resistance of glioma cells in vitro and in vivo. FOXD2-AS1 was highly expressed in glioma cell lines, and its expression was suppressed by curcumol treatment in a dose- and time-dependent manner. The forced expression of FOXD2-AS1 abrogated the effect of curcumol on glioma cell proliferation, metastasis, self-renewal ability, and TMZ resistance. Moreover, the forced expression of FOXD2-AS1 reversed the inhibitory effect of curcumol on EZH2 activation.Conclusions: We showed for the first time that curcumol is effective in inhibiting malignant biological behaviors and TMZ-resistance of glioma cells by suppressing FOXD2-AS1-mediated EZH2 activation on anti-oncogenes. Our findings offer the possibility of exploiting curcumol as a promising therapeutic agent for glioma treatment and may provide an option for the clinical application of this natural herbal medicine.

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