Mechanism of Hypoxia-Activated MiR-194 /FoxO3a Inducing Glycolytic Metabolism Reprogramming in Gastric Precancerous Lesions

Abstract Background: Early diagnosis and treatment of gastric precancerous lesions (GPL) are key factors for reducing the incidence and morbidity of gastric cancer. The study aimed to examine GPL in mice induced by MNU and to illustrate the underlying mechanisms of tumorigenesis.Methods: In this study, we utilized an in vivo MNU (N-methyl-N-nitroso-urea)-induced GPL mouse model, Histopathological changes of the gastric mucosa were observed by Hematoxylin and Eosin (H&E-stain) and alcian blue (AB-PAS-stain); The level of miR-194-5p in the gastric mucosa were determined by real‐time polymerase chain reaction; We used transmission electron microscopy to observe the effects of MNU on gastric chief cells and parietal cells; We performed immunohistochemical detection of HIF-1α, vWF, Ki-67 and P53, while the changes in protein expression of key genes in LKB1-AMPK and AKT-FoxO3 signaling pathways were detected by western blot analysis.Results: We demonstrated that miR-194-5p expression was upregulated under hypoxia in GPL gastric tissues, and that a high miR-194-5p expression level closely related with tumorigenesis. Mechanistically, miR-194-5p exerted the acceleration of activities related to metabolic reprogramming through LKB1-AMPK and AKT-FoxO3 pathways. Furthermore, similar to miR-194-5p, high expression levels of AMPK and AKT were also related to the metabolic reprogramming of GPL. Moreover, we revealed the correlation between the expression levels of miR-194-5p, p-AMPKα, p-AKT, and FoxO3a. Conclusions: These findings suggest that miR-194-5p/FoxO3 pathway is important for the reversal of metabolic reprogramming in GPL. Thus, exploring strategies to regulate the miR-194-5p/FoxO3a pathway may provide an efficient strategy for the prevention and treatment of GPL.

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Weipiling ameliorates gastric precancerous lesions in Atp4a−/− mice

BMC Complementary and Alternative Medicine ◽

10.1186/s12906-019-2718-y ◽

2019 ◽

Vol 19 (1) ◽

Author(s):

Wei Liu ◽

Zi-ming Zhao ◽

Yuan-liang Liu ◽

Hua-feng Pan ◽

Li-zhu Lin

Keyword(s):

Gastric Mucosa ◽

Precancerous Lesions ◽

Tunel Staining ◽

Model Group ◽

Ki 67 ◽

Protein Levels ◽

Chinese Medicine Formula ◽

Pas Staining ◽

Different Doses

Abstract Background Altered cellular metabolism is considered to be one of the hallmarks of cancer (Coller, Am J Pathol 184:4–17, 2014; Kim and Bae, Curr Opin Hematol 25:52–59, 2018). However, few studies have investigated the role of metabolism in the development of gastric precancerous lesions (GPLs). Weipiling (WPL), a traditional Chinese medicine formula for treatment of GPLs. In this study, we evaluated the amelioration of GPLs by WPL and investigated the possible role of WPL in regulating glucose metabolism. Methods Firstly, the major components of WPL are chemically characterized by HPLC analytical method. In this study, we chose the Atp4a−/− mouse model (Spicer etal., J Biol Chem 275:21555–21565, 2000) for GPL analysis. Different doses of WPL were administered orally to mice for 10 weeks. Next, the pathological changes of gastric mucosa were assessed by the H&E staining and AB-PAS staining. In addition, TUNEL staining was used to evaluate apoptosis, and we further used immunohistochemically labelled CDX2, MUC2, ki-67, PTEN, and p53 proteins to assess the characteristic changes of gastric mucosa in precancerous lesions. The levels of such transporters as HK-II, PKM2, ENO1, MPC1, and LDHA were determined by Western blot analysis. Finally, we assessed the expression of mTOR, HIF-1α, AMPK, Rheb, TSC1 and TSC2 protein in the gastric mucosa of Atp4a−/−mice. Results In this work, we evaluated the protective effect of WPL on gastric mucosa in mice with precancerous lesions. The aberrant apoptosis in gastric mucosa of gastric pre-cancerous lesions was controlled by WPL (P<0.05). Furthermore, WPL suppressed the expression of CDX2, MUC2, ki-67, PTEN and p53, as the levels of these proteins decreased significantly compared with the model group (P<0.05). In parallel, WPL significantly suppressed the expression of transporters, such as HK-II, PKM2, ENO1, MPC1 and LDHA (P<0.05). In addition, mTOR, HIF-1a, AMPK, Rheb, TSC1 and TSC2 protein levels in gastric mucosa of Atp4a−/− mice in the high- and low-dose WPL groups were significantly lower than those in the model group (P<0.05), while the expression of TSC1 and TSC2 protein was significantly higher (P<0.05). Conclusions Conclusively, WPL could ameliorate GPLs in Atp4a−/− mice by inhibiting the expression of transporters and suppressing the aberrant activation of mTOR/HIF-1α.

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Binding Specificity of Radiolabeled Cyclic Peptide 153Sm-DTPA-c(CGRRAGGSC) to MHCC97-H Human Liver Cancer Cells and its Antitumor Effects in vivo

Technology in Cancer Research & Treatment ◽

10.1177/1533034615604785 ◽

2016 ◽

Vol 15 (6) ◽

pp. NP1-NP9

Author(s):

Qinghua Wu ◽

Yujie He ◽

Chen Gu ◽

Jianwei Jiang ◽

Huan Zhou ◽

...

Keyword(s):

Human Liver ◽

Cyclic Peptide ◽

Expression Levels ◽

Liver Cancer Cells ◽

Human Liver Cancer ◽

Hematoxylin And Eosin ◽

Hematoxylin And Eosin Staining ◽

Human Liver Cancer Cells ◽

Interleukin 11

Objective: This objective of this study is to investigate the effects of the radiolabeled cyclic peptide 153Sm-DTPA-c(CGRRAGGSC) on MHCC97-H human liver cancer cells in vitro and in vivo. Methods: The protein expression levels were examined by Western blot analysis. Biological activity of 153Sm-DTPA-c(CGRRAGGSC) was assessed with the radioligand binding assay and competitive inhibition experiment. Subcellular localization of the cyclic peptide was observed by fluorescence microscopy. Animals were implanted with MHCC97-H cells and administered with 153Sm-DTPA-c(CGRRAGGSC). Hematoxylin and eosin staining, electron microscopy, and immunohistochemistry were performed to evaluate the effects of 153Sm-DTPA-c(CGRRAGGSC) on implanted tumors. Result: The expression levels of interleukin 11 receptor were significantly elevated, by 2-to 5-fold, in tumor cell lines, especially for MHCC97-H cells. Characterization of 153Sm-DTPA-c(CGRRAGGSC) showed that the biological activity of the cyclic peptide was not altered after labeling, and the radiolabeled cyclic peptide exhibited sufficient binding affinity to interleukin 11 receptor . The cyclic peptide of c(CGRRAGGSC) was mainly distributed in the cytoplasm and on the cell membrane of MHCC97-H cells. The in vivo experiments showed that the tumor growth was significantly inhibited by the treatment of 153Sm-DTPA-c(CGRRAGGSC). The inhibitory effect of 153Sm-DTPA-c(CGRRAGGSC) on tumor growth was further confirmed by Hematoxylin and eosin staining, electron microscopy, and immunohistochemistry. Moreover, the expression levels of interleukin 11 receptor in implanted tumors were significantly decreased in the treatment groups. Conclusion: 153Sm-DTPA-c (CGRRAGGSC) could specifically bind to interleukin 11 receptor on MHCC97-H liver tumor cells, inhibiting the cell proliferation and inducing cellular apoptosis. These findings provide experimental evidence for the development of individual treatment of liver cancers, as well as recurrence and metastasis.

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Tissue-infiltrating macrophages mediate an exosome-based metabolic reprogramming upon DNA damage

Nature Communications ◽

10.1038/s41467-019-13894-9 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 13

Author(s):

Evi Goulielmaki ◽

Anna Ioannidou ◽

Maria Tsekrekou ◽

Kalliopi Stratigi ◽

Ioanna K. Poutakidou ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Glucose Transporter ◽

Ex Vivo ◽

Disease Onset ◽

Metabolic Reprogramming ◽

Inflammatory Stimuli ◽

Underlying Mechanisms ◽

Repair Defect

AbstractDNA damage and metabolic disorders are intimately linked with premature disease onset but the underlying mechanisms remain poorly understood. Here, we show that persistent DNA damage accumulation in tissue-infiltrating macrophages carrying an ERCC1-XPF DNA repair defect (Er1F/−) triggers Golgi dispersal, dilation of endoplasmic reticulum, autophagy and exosome biogenesis leading to the secretion of extracellular vesicles (EVs) in vivo and ex vivo. Macrophage-derived EVs accumulate in Er1F/− animal sera and are secreted in macrophage media after DNA damage. The Er1F/− EV cargo is taken up by recipient cells leading to an increase in insulin-independent glucose transporter levels, enhanced cellular glucose uptake, higher cellular oxygen consumption rate and greater tolerance to glucose challenge in mice. We find that high glucose in EV-targeted cells triggers pro-inflammatory stimuli via mTOR activation. This, in turn, establishes chronic inflammation and tissue pathology in mice with important ramifications for DNA repair-deficient, progeroid syndromes and aging.

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CISD3 inhibition drives cystine-deprivation induced ferroptosis

Cell Death and Disease ◽

10.1038/s41419-021-04128-2 ◽

2021 ◽

Vol 12 (9) ◽

Author(s):

Yanchun Li ◽

Xin Wang ◽

Zhihui Huang ◽

Yi Zhou ◽

Jun Xia ◽

...

Keyword(s):

Lipid Peroxidation ◽

Cell Death ◽

Cancer Progression ◽

Ectopic Expression ◽

Pathological Process ◽

Metabolic Reprogramming ◽

Regulatory Role ◽

Underlying Mechanisms

AbstractFerroptosis, a new form of programmed cell death, not only promotes the pathological process of various human diseases, but also regulates cancer progression. Current perspectives on the underlying mechanisms remain largely unknown. Herein, we report a member of the NEET protein family, CISD3, exerts a regulatory role in cancer progression and ferroptosis both in vivo and in vitro. Pan-cancer analysis from TCGA reveals that expression of CISD3 is generally elevated in various human cancers which are consequently associated with a higher hazard ratio and poorer overall survival. Moreover, knockdown of CISD3 significantly accelerates lipid peroxidation and accentuates free iron accumulation triggered by Xc– inhibition or cystine-deprivation, thus causing ferroptotic cell death. Conversely, ectopic expression of the shRNA-resistant form of CISD3 (CISD3res) efficiently ameliorates the ferroptotic cell death. Mechanistically, CISD3 depletion presents a metabolic reprogramming toward glutaminolysis, which is required for the fuel of mitochondrial oxidative phosphorylation. Both the inhibitors of glutaminolysis and the ETC process were capable of blocking the lipid peroxidation and ferroptotic cell death in the shCISD3 cells. Besides, genetic and pharmacological activation of mitophagy can rescue the CISD3 knockdown-induced ferroptosis by eliminating the damaged mitochondria. Noteworthily, GPX4 acts downstream of CISD3 mediated ferroptosis, which fails to reverse the homeostasis of mitochondria. Collectively, the present work provides novel insights into the regulatory role of CISD3 in ferroptotic cell death and presents a potential target for advanced antitumor activity through ferroptosis.

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Inhibition of KIF14 Suppresses Tumor Cell Growth and Promotes Apoptosis in Human Glioblastoma

Cellular Physiology and Biochemistry ◽

10.1159/000438532 ◽

2015 ◽

Vol 37 (5) ◽

pp. 1659-1670 ◽

Cited By ~ 12

Author(s):

Wei Huang ◽

JunYu Wang ◽

Danfeng Zhang ◽

Wen Chen ◽

Lijun Hou ◽

...

Keyword(s):

Normal Brain ◽

Ki 67 ◽

Akt Phosphorylation ◽

M Phase ◽

Underlying Mechanisms ◽

Sirna Knockdown ◽

Kinesin Superfamily

Background/Aims: The mitotic kinesin superfamily protein KIF14 is essential for cytokinesis and chromosome segregation, and increased KIF14 expression is related to a variety of human cancers. However, the role of KIF14 in the development and malignant progression of astrocytomas and the underlying mechanisms remain unclear. The present study examined the relation between KIF14 and the pathogenesis of malignant astrocytoma. Methods and Results: The role of KIF14 in astrocytoma development and progression was investigated by analyzing KIF14 expression using SYBR Green quantitative real-time RT-PCR, western blotting and immunohistochemistry in human astrocytoma and normal brain tissues. KIF14 expression was higher in astrocytoma samples, and was positively correlated with pathological grade and proliferative activity indicated by Ki-67 staining. SiRNA knockdown of KIF14 inhibited tumor growth in vitro and in vivo, attenuated anchorage-independent growth, and induced G2/M phase arrest, cytokinesis failure and apoptosis in glioblastoma cell lines in association with decreased AKT phosphorylation and activity. Conclusions: The upregulation of KIF14 in astrocytoma is associated with disease severity, and suppression of KIF14 inhibits cell proliferation and induces apoptosis through a mechanism involving the inactivation of AKT signaling, suggesting that KIF14 plays an important role in astrocytoma tumorigenesis and could be a promising molecular target for anticancer therapy.

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Exosome-mediated transfer of microRNAs promotes mouse iPSCs differentiation into therapeutic insulin-producing cells

10.21203/rs.3.rs-561531/v1 ◽

2021 ◽

Author(s):

Qingsong Guo ◽

Yuhua Lu ◽

Yan Huang ◽

Yibing Guo ◽

Shajun Zhu ◽

...

Keyword(s):

Gene Expression ◽

Diabetic Mouse ◽

Min6 Cells ◽

Argonaute 2 ◽

Insulin Producing Cells ◽

Transmission Electron ◽

Exosomal Mirnas ◽

Underlying Mechanisms ◽

Mirnas Expression

Abstract Purpose Exosome-based therapeutic approaches have been applied in diabetes. In the present study, we explored the effect of exosomes on iPSCs differentiation into insulin-producing cells and its underlying mechanisms. Methods Exosomes were isolated by ultracentrifugation from MIN6 cells and identified by Transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and Western blot. PKH67 tracer and transwell assay were used to confirm exosome delivery into iPSCs. QRT-PCR was applied to detect key pancreatic gene expression and miRNAs expression in differentiated iPSCs. Insulin expression was assessed by flow cytometry (FCM) and immunofluorescence. The mechanism underlying exosome induction capacity for iPSCs was determined via RNA-interference of Argonaute-2 (Ago2). Streptozotozin(STZ) was used to establish diabetic mouse model to verify the function of differentiated β-like cells. Results MIN6-derived exosomes promoted the key pancreatic gene expression and immunofluorescence for Nkx6.1 and insulin remarkably, confirming the capability of exosomes for iPSCs differentiation. Moreover, transplantation of differentiated iPSCs efficiently enhanced IPGTT and partially control hyperglycemia in T1D mice. Knockdown of Ago2 in MIN6 cells affect exosomal miRNAs expression and pancreatic gene expression and insulin secretion in iPSCs.The therapeutic effect in vivo was weakened, further indicating decreased exosomal miRNA affect iPSCs differentiation.7 specific exosomal miRNAs were selected for single-assay validation. MiR-706, miR-709, miR-466c-5p and miR-423-5p were found dynamic changed during differentiation stages. Conclusion Exosomes is an effective and convenient induction approach for iPSCs differentiation into functional insulin secreting cells.The effect was downregulated via Ago2 knockdown illustrates the mechanisms are highly relevant to specific miRNAs enriched in exosomes.

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Zirconia Nanoparticles Induce HeLa Cell Death Through Mitochondrial Apoptosis and Autophagy Pathways Mediated by ROS

Frontiers in Chemistry ◽

10.3389/fchem.2021.522708 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yinghui Shang ◽

Qinghai Wang ◽

Jian Li ◽

Haiting Liu ◽

Qiangqiang Zhao ◽

...

Keyword(s):

Cell Death ◽

Hela Cell ◽

Hela Cells ◽

Mitochondrial Apoptosis ◽

Ki 67 ◽

Transmission Electron ◽

Anti Tumor Activity ◽

Zirconia Nanoparticles

Zirconia nanoparticles (ZrO2 NPs) are commonly used in the field of biomedical materials, but their antitumor activity and mechanism is unclear. Herein, we evaluated the anti-tumor activity of ZrO2 NPs and explored the anti-tumor mechanism. The results of in vitro and in vivo experiments showed that the level of intracellular reactive oxygen species (ROS) in HeLa cells was elevated after ZrO2 NPs treatment. Transmission electron microscopy (TEM) showed that after treatment with ZrO2 NPs, the mitochondria of HeLa cells were swollen, accompanied with the induction of autophagic vacuoles. In addition, flow cytometry analysis showed that the apoptotic rate of HeLa cells increased significantly by Annexin staining after treatment with ZrO2 NPs, and the mitochondrial membrane potential (MMP) was reduced significantly. The proliferation of HeLa cells decreased as indicated by reduced Ki-67 labeling. In contrast, TUNEL-positive cells in tumor tissues increased after treatment with ZrO2 NPs, which is accompanied by increased expression of mitochondrial apoptotic proteins including Bax, Caspase-3, Caspase-9, and Cytochrome C (Cyt C) and increased expression of autophagy-related proteins including Atg5, Atg12, Beclin-1, and LC3-II. Treating HeLa cells with N-acetyl-L-cysteine (NAC) significantly reduced ROS, rate of apoptosis, MMP, and in vivo anti-tumor activity. In addition, apoptosis- and autophagy-related protein expressions were also suppressed. Based on these observations, we conclude that ZrO2 NPs induce HeLa cell death through ROS mediated mitochondrial apoptosis and autophagy.

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HSP90α Mediates Sorafenib Resistance in Human Hepatocellular Carcinoma by Necroptosis Inhibition under Hypoxia

Cancers ◽

10.3390/cancers13020243 ◽

2021 ◽

Vol 13 (2) ◽

pp. 243

Author(s):

Yan Liao ◽

Yue Yang ◽

Di Pan ◽

Youxiang Ding ◽

Heng Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Imaging System ◽

Morphological Changes ◽

Critical Role ◽

Tumor Xenograft ◽

Target Drug ◽

Transmission Electron ◽

Underlying Mechanisms

As one of the most common malignancies worldwide, Hepatocellular carcinoma (HCC) has been treated by Sorafenib, which is the first approved target drug by FDA for advanced HCC. However, drug resistance is one of the obstacles to its application. As a typical characteristic of most solid tumors, hypoxia has become a key cause of resistance to chemotherapy and radiotherapy. It is important to elucidate the underlying mechanisms of Sorafenib resistance under hypoxia. In this study, the morphological changes of hepatocellular carcinoma cells were observed by Live Cell Imaging System and Transmission Electron Microscope; Sorafenib was found to induce necroptosis in liver cancer. Under hypoxia, the distribution of necroptosis related proteins was changed, which contributed to Sorafenib resistance. HSP90α binds with the necrosome complex and promotes chaperone-mediated autophagy (CMA) degradation, which leads necroptosis blocking and results in Sorafenib resistance. The patient-derived tumor xenograft (PDX) model has been established to investigate the potential therapeutic strategies to overcome Sorafenib resistance. 17-AAG inhibited HSP90α and presented obvious reversal effects of Sorafenib resistance in vivo and in vitro. All the results emphasized that HSP90α plays a critical role in Sorafenib resistance under hypoxia and 17-AAG combined with Sorafenib is a promising therapy for hepatocellular carcinoma.

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TOP2A/MCM2, p16INK4a, and cyclin E1 expression in liquid-based cytology: a biomarkers panel for progression risk of cervical premalignant lesions

BMC Cancer ◽

10.1186/s12885-020-07740-1 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Oscar Del Moral-Hernández ◽

Daniel Hernández-Sotelo ◽

Luz del Carmen Alarcón-Romero ◽

Miguel Angel Mendoza-Catalán ◽

Eugenia Flores-Alfaro ◽

...

Keyword(s):

Cervical Cancer ◽

Precancerous Lesions ◽

Premalignant Lesions ◽

Low Grade ◽

Squamous Intraepithelial Lesions ◽

Ki 67 ◽

Expression Levels ◽

Cyclin E1 ◽

Liquid Based Cytology ◽

Intraepithelial Lesions

Abstract Background To improve the efficiency of early diagnosis systems for cervical cancer, the use of cellular and viral markers for identifying precancerous lesions with a greater probability to progress to cancer has been proposed. Several cellular proteins and markers of oxidative DNA damage have been suggested as possible biomarkers of cervical carcinogenesis; however, they have not been evaluated together. In this study, we analyzed the expression of the cellular markers p16INK4a, Ki-67, CyclinE1, TOP2A/MCM2, and telomerase, as well as the DNA oxidative damage markers ROS and 8-OHdG. The analyses were performed in liquid-based cervical cytology samples or biopsies with premalignant lesions or cervical cancer diagnosis, with the purpose of selecting a panel of biomarkers that allow the identification of precursor lesions with greater risk of progression to cervical cancer. Methods We analyzed 1485 liquid-based cytology samples, including 239 non-squamous intraepithelial lesions (NSIL), 901 low-grade squamous intraepithelial lesions (LSIL), 54 high-grade squamous intraepithelial lesions (HSIL), and 291 cervical cancers (CC). The biomarkers were analyzed by immunocytochemistry and Human Papilloma Virus (HPV) genotyping with the INNO-LiPA genotyping Extra kit. Results We found that all tested cellular biomarkers were overexpressed in samples with high risk-HPV infection, and the expression levels increased with the severity of the lesion. TOP2A/MCM2 was the best biomarker for discriminating between LSIL and HSIL, followed by p16INK4a and cyclinE1. Statistical analysis showed that TOP2A/MCM2 provided the largest explanation of HSIL and CC cases (93.8%), followed by p16INK4a (91%), cyclin E1 (91%), Ki-67 (89.3%), and telomerase (88.9%). Conclusions We propose that the detection of TOP2A/MCM2, p16INK4a and cyclin E1 expression levels is useful as a panel of biomarkers that allow identification of cervical lesions with a higher risk for progression to CC with high sensitivity and precision; this can be done inexpensively, in a single and non-invasive liquid-based cytology sample.

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circEVI5 acts as a miR-4793-3p sponge to suppress the proliferation of gastric cancer

Cell Death and Disease ◽

10.1038/s41419-021-04061-4 ◽

2021 ◽

Vol 12 (8) ◽

Author(s):

Meinan Yan ◽

Liling Niu ◽

Jing Liu ◽

Yuan Yao ◽

Hui Li

Keyword(s):

Gastric Cancer ◽

Cell Cycle ◽

Circular Rnas ◽

Tissue Samples ◽

Expression Levels ◽

Rna Immunoprecipitation ◽

Incorporation Assay ◽

Underlying Mechanisms

AbstractCircular RNAs (circRNAs) are a novel class of endogenous noncoding RNAs (ncRNAs) with a covalently closed loop structure. Accumulating evidence shows that circRNAs play vital roles in the growth, metastasis, treatment and prognosis of various cancers. However, the detailed functions and underlying mechanisms of circEVI5 (hsa_circ_0013162) in gastric cancer (GC) remain undocumented. In this study, the expression levels and prognostic value of circEVI5 were validated in GC tissue samples by using qRT-PCR. circEVI5 was significantly downregulated in GC tissues and cells, and low circEVI5 expression was correlated with poor prognosis. Next, in vitro CCK-8 assay, EdU incorporation assay, PI staining cell cycle assay, and in vivo xenograft mouse models were conducted to assess the functions of circEVI5. Gain of function experiments indicated that circEVI5 could inhibit GC cell proliferation and retard the cell cycle. Moreover, bioinformatics prediction showed that circEVI5 binds to miR-4793-3p, while FOXO1 may be a target of miR-4793-3p. Pull-down assays, RNA immunoprecipitation (RIP) assays, luciferase assays, and western blot were used to confirm the interactions between circEVI5, miR-4793-3p, and FOXO1. Functional assays demonstrated that circEVI5 suppressed the proliferation of GC by sponging miR-4793-3p and increasing FOXO1 expression levels. In conclusion, our study demonstrated that circEVI5 can bind miR-4793-3p as a ceRNA to eliminate the negative regulation of FOXO1, therefore suppressing GC proliferation.

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