scholarly journals Hypoxia-Induced PTTG3P Contributes to Colorectal Cancer Glycolysis and M2 Phenotype of Macrophage

2021 ◽  
Author(s):  
yue wang ◽  
guilin yu ◽  
yiyang liu ◽  
longfei xie ◽  
jinnian ge ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Malignant Tumors ◽  
Macrophage Polarization ◽  
Ectopic Expression ◽  
Loss Of Function ◽  
Mice Model ◽  
Atp Assay ◽  
Dismal Prognosis ◽  
Novel Approach ◽  
M2 Phenotype

Abstract Background Long noncoding RNAs (lncRNAs) play critical factors in tumor progression and are ectopically expressed in malignant tumors. Until now, lncRNA PTTG3P biological function in colorectal cancer (CRC) needs further to be clarified. Methods qRT-PCR was used to measure the PTTG3P level and CCK-8, glucose uptake, lactate assay, ATP assay, ECAR assay, and xenograft mice model were adopted to evaluate the glycolysis and proliferation, and macrophage polarization were determined in CRC cells. Xenograft experiments were utilized to analyze tumor growth. Results Ectopic expression of PTTG3P was involved in CRC and related to dismal prognosis. Through gain-of-function and loss-of-function approaches, PTTG3P enhanced cell proliferation and glycolysis through YAP1. Further, LDHA knockdown or glycolysis inhibitor (2-DG,3-BG) recovered PTTG3P-induced proliferation. And PTTG3P overexpression could facilitate M2 polarization of macrophages. Silenced PTTG3P decreased the level of inflammatory cytokines TNF-α, IL-1β, and IL-6, and low PTTG3P expression related with CD8+ T, NK, and TFH cell infiltration. Besides, HIF1A could increase PTTG3P expression by binding to the PTTG3P promoter region. Conclusions Hypoxia-induced PTTG3P contributes to glycolysis and M2 phenotype of macrophage, which proposes a novel approach for clinical treatment.

scholarly journals Hypoxia-induced PTTG3P contributes to colorectal cancer glycolysis and M2 phenotype of macrophage

2021 ◽  
Author(s):  
Yue Wang ◽  
Guilin Yu ◽  
Yiyang Liu ◽  
Longfei Xie ◽  
Jinnian Ge ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Malignant Tumors ◽  
Macrophage Polarization ◽  
Ectopic Expression ◽  
Loss Of Function ◽  
Mice Model ◽  
Atp Assay ◽  
Dismal Prognosis ◽  
Novel Approach ◽  
M2 Phenotype

Long noncoding RNAs (lncRNAs) play critical factors in tumor progression and are ectopically expressed in malignant tumors. Until now, lncRNA PTTG3P biological function in colorectal cancer (CRC) needs further to be clarified. qRT-PCR was used to measure the PTTG3P level and CCK-8, glucose uptake, lactate assay, ATP assay, ECAR assay, and xenograft mice model were adopted to evaluate the glycolysis and proliferation, and macrophage polarization were determined in CRC cells. Xenograft experiments were utilized to analyze tumor growth. Ectopic expression of PTTG3P was involved in CRC and related to dismal prognosis. Through gain-of-function and loss-of-function approaches, PTTG3P enhanced cell proliferation and glycolysis through YAP1. Further, LDHA knockdown or glycolysis inhibitor (2-DG,3-BG) recovered PTTG3P-induced proliferation. And PTTG3P overexpression could facilitate M2 polarization of macrophages. Silenced PTTG3P decreased the level of inflammatory cytokines TNF-α, IL-1β, and IL-6, and low PTTG3P expression related with CD8+ T, NK, and TFH cell infiltration. Besides, HIF1A could increase PTTG3P expression by binding to the PTTG3P promoter region. Hypoxia-induced PTTG3P contributes to glycolysis and M2 phenotype of macrophage, which proposes a novel approach for clinical treatment.

N6-Methyladenosine Modification of PTTG3P Contributes to Colorectal Cancer Progression via IGF2BP2

2021 ◽  
Author(s):  
yang zheng ◽  
guilin yu ◽  
longfei xie ◽  
yue wang ◽  
guohua zhao
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Hippo Pathway ◽  
Predictive Ability ◽  
Predictive Biomarker ◽  
Receiver Operating Curve ◽  
Loss Of Function ◽  
Mice Model ◽  
Atp Assay ◽  
Rna Immunoprecipitation

Abstract Background N6-methyladenosine (m6A) and long noncoding RNAs (lncRNAs) emerged as crucial players in colorectal cancer (CRC) progression, but the m6A modified lncRNA PTTG3P in CRC are still need to be systematically defined. Methods qRT-PCR was adopted to measure the PTTG3P expression. Survival analysis was used to explore the correlation between the expression of PTTG3P and CRC patients prognosis. Receiver operating curve (ROC) was tested to evaluate the PTTG3P predictive ability. Functional studies were examined by CCK-8, glucose uptake, lactate assay, ATP assay, ECAR assay and xenograft mice model. Mechanistic studies were explored by GSEA, methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and RNA immunoprecipitation (RIP).Results PTTG3P was upregulated in CRC and closely related to poor prognosis. Through gain and loss of function approaches, PTTG3P facilitated proliferation and glycolysis through Hippo pathway, and glycolysis inhibitor (2-DG ,3-BG) and LDHA knockdown could rescue cell proliferation. Mechanically, m6A methylation induced the elevation of PTTG3P by increasing its stability , and insulin like growth factor-2 mRNA binding proteins 2 (IGF2BP2) involved in the progression. Finally, rescue assays validated the effect of METTL3/PTTG3P/YAP1 axis in CRC progression. Conclusions m6A-induced PTTG3P could facilitates CRC development via interacting with IGF2BP2, which provides a predictive biomarker and theraperutic target for CRC.

scholarly journals A FoxM1/lncRNA PTTG3P/YAP1 Positive Feedback Loop Controls Colorectal Cancer Progression

2021 ◽  
Author(s):  
Yang zheng ◽  
Guilin yu ◽  
Yiyang Liu ◽  
Longfei Xie ◽  
Jinnian Ge ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Positive Feedback ◽  
Promoter Region ◽  
Feedback Loop ◽  
Ectopic Expression ◽  
Luciferase Assay ◽  
Mice Model ◽  
Positive Feedback Loop ◽  
Dismal Prognosis

Abstract Background Pseudogenes are vital regulators of cancer progression. PTTG3P biological function in colorectal cancer (CRC) needs further to be clarified. Methods qRT-PCR was adopted to measure the PTTG3P expression. Functional studies were examined by CCK-8, glucose uptake, lactate assay, ATP assay, ECAR assay and xenograft mice model. The mechanism of PTTG3P was carried by GSEA. Chromatin immunoprecipitation (ChIP) and luciferase assay were explored to certify the binding activity between PTTG3P promoter region and FoxM1. Results Ectopic expression of PTTG3P was involved in CRC and related to dismal prognosis. Experimental evidence discovered that PTTG3P enhanced cell proliferation and glycolysis through YAP1 and regulated FoxM1(Hippo pathway target gene). Further, LDHA knockdown or glycolysis inhibitor (2-DG,3-BG) recovered PTTG3P-induced proliferation. Mechanically, FoxM1 increase PTTG3P expression at transcription level and the PTTG3P promoter region of -900 to -1200 nt is necessary for binding with FoxM1, thus forming a positive feedback loop to facilitates the CRC progression. Additionally, FoxM1 depletion could rescue the PTTG3P function. Conclusions A FoxM1/lncRNA PTTG3P/YAP1 positive feedback loop plays a vital part in CRC progression, and targeting FoxM1, PTTG3P and YAP1 provides therapeutic targets for CRC treatment.

scholarly journals Alterations in ZnT1 expression and function lead to impaired intracellular zinc homeostasis in cancer

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Adrian Israel Lehvy ◽  
Guy Horev ◽  
Yarden Golan ◽  
Fabian Glaser ◽  
Yael Shammai ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
Zinc Homeostasis ◽  
Healthy Population ◽  
Missense Mutations ◽  
Protein Alignment ◽  
Loss Of Function ◽  
Intracellular Zinc ◽  
Dismal Prognosis ◽  
Zinc Levels ◽  
And Function

Abstract Zinc is vital for the structure and function of ~3000 human proteins and hence plays key physiological roles. Consequently, impaired zinc homeostasis is associated with various human diseases including cancer. Intracellular zinc levels are tightly regulated by two families of zinc transporters: ZIPs and ZnTs; ZIPs import zinc into the cytosol from the extracellular milieu, or from the lumen of organelles into the cytoplasm. In contrast, the vast majority of ZnTs compartmentalize zinc within organelles, whereas the ubiquitously expressed ZnT1 is the sole zinc exporter. Herein, we explored the hypothesis that qualitative and quantitative alterations in ZnT1 activity impair cellular zinc homeostasis in cancer. Towards this end, we first used bioinformatics to analyze inactivating mutations in ZIPs and ZNTs, catalogued in the COSMIC and gnomAD databases, representing tumor specimens and healthy population controls, respectively. ZnT1, ZnT10, ZIP8, and ZIP10 showed extremely high rates of loss of function mutations in cancer as compared to healthy controls. Analysis of the putative functional impact of missense mutations in ZnT1-ZnT10 and ZIP1-ZIP14, using homologous protein alignment and structural predictions, revealed that ZnT1 displays a markedly increased frequency of predicted functionally deleterious mutations in malignant tumors, as compared to a healthy population. Furthermore, examination of ZnT1 expression in 30 cancer types in the TCGA database revealed five tumor types with significant ZnT1 overexpression, which predicted dismal prognosis for cancer patient survival. Novel functional zinc transport assays, which allowed for the indirect measurement of cytosolic zinc levels, established that wild type ZnT1 overexpression results in low intracellular zinc levels. In contrast, overexpression of predicted deleterious ZnT1 missense mutations did not reduce intracellular zinc levels, validating eight missense mutations as loss of function (LoF) mutations. Thus, alterations in ZnT1 expression and LoF mutations in ZnT1 provide a molecular mechanism for impaired zinc homeostasis in cancer formation and/or progression.

scholarly journals MicroRNA-720 suppresses M2 macrophage polarization by targeting GATA3

2016 ◽  
Vol 36 (4) ◽  
Author(s):  
Yan Zhong ◽  
Chun Yi
Keyword(s):  
Macrophage Polarization ◽  
Ectopic Expression ◽  
Tumour Microenvironment ◽  
M2 Macrophage ◽  
Breast Carcinomas ◽  
Downstream Target ◽  
M2 Polarization ◽  
M2 Macrophage Polarization ◽  
And Function ◽  
M2 Phenotype

Macrophages are highly plastic cells with the ability to differentiate into both M1- and M2-polarized phenotypes. As a distinct M2-polarized population, tumour-associated macrophages (TAMs) promote tumorigenesis owing to their pro-angiogenic and immune-suppressive functions in tumour microenvironment. In the present study, we found that the microRNA-720 (miR-720) was down-regulated in TAMs isolated from breast carcinomas and M2-polarization macrophages. Overexpression of miR-720 attenuated M2 phenotype expression and thus inhibited M2 polarization. We further identified GATA binding protein 3 (GATA3), a transcriptional factor that plays an important role in M2 macrophage polarization, was the downstream target of miR-720. Ectopic expression of GATA3 restored the M2 phenotype in miR-720 overexpressed macrophages. Importantly, overexpression of miR-720 inhibited pro-migration behaviour and phagocytic ability of M2-polarized macrophages. Thus, our data suggest that miR-720 plays an important role in regulating M2 macrophage polarization and function.

scholarly journals The role of XBP-1-mediated unfolded protein response in colorectal cancer progression-a regulatory mechanism associated with lncRNA-miRNA-mRNA network

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yong Wang ◽  
Jingyu Zhang ◽  
Shuang Zheng
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Cancer Progression ◽  
Cell Apoptosis ◽  
Regulatory Mechanism ◽  
Luciferase Reporter ◽  
Loss Of Function ◽  
Mice Model

Abstract Background We aim to identify the expression and analyze the molecular action of dysregulated lncRNA-miRNA mediated by XBP-1 in colorectal cancer (CRC). Methods Here, we identified XBP-1-mediated dysregulated lncRNAs and miRNAs in CRC by bioinformatics analysis. The expression level of lncRNAs and miRNA was measured using quantitative real time PCR, and the expression of XBP-1, as well as apoptosis-related proteins, were detected by western blot. CCK-8 and TUNEL assays were performed to determine cell proliferation and apoptosis, respectively. Luciferase reporter assay was conducted to verify the binding relationship among lncRNA-miRNA-XBP-1. BALB/c nude mice were inoculated subcutaneously with HCT116 cells to establish tumor-bearing mice model. Histological analysis was carried out by HE staining and immunohistochemical staining. Results Six downregulated lncRNAs (SLFNL1-AS1, KCNQ1OT1, NEAT1, XIST, AC016876.2, AC026362.1), four dysregulated miRNAs (miR-500a-3p, miR-370-3p, miR-2467-3p, miR-512-3p) and upregulated XBP-1 were identified in CRC cell lines. Gain- and loss-of-function experiments showed that overexpression of KCNQ1OT1/XIST promoted cell proliferation and suppressed cell apoptosis. In addition, overexpression of KCNQ1OT1/XIST partly abolished the inhibitory effects of XBP-1u knockdown or tunicamycin, an activator of endoplasmic reticulum stress, on CRC cell viability loss and apoptosis. Furthermore, KCNQ1OT1/XIST aggravated tumor growth in vivo by regulating endoplasmic reticulum stress and cell apoptosis. Conclusions This study has constructed lncRNA-miRNA-mRNA networks based on XBP-1 in CRC, and disclosed the regulatory mechanism of action, providing a set of pivotal biomarkers for future molecular investigation and targeted treatment of CRC.

scholarly journals Decreased level of miR-1301 promotes colorectal cancer progression via activation of STAT3 pathway

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Fangfang Yang ◽  
Hua Wang ◽  
Bianbian Yan ◽  
Tong Li ◽  
Lulu Min ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Migration ◽  
Cancer Progression ◽  
Luciferase Assay ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Aberrant Expression ◽  
Cell Migration And Invasion ◽  
Lovo Cells ◽  
Colorectal Cancer Progression

Abstract The molecular pathogenesis of colorectal cancer (CRC) has been widely investigated in recent years. Accumulating evidence has indicated that microRNA (miRNA) dysregulation participates in the processes of driving CRC initiation and progression. Aberrant expression of miR-1301 has been found in various tumor types. However, its role in CRC remains to be elucidated. In the present study, we identified miR-1301 was enriched in normal colorectal tissues and significantly down-regulated in CRC. Decreased level of miR-1301 strongly correlated with aggressive pathological characteristics, including advanced stage and metastasis. Bioinformatics and dual luciferase assay demonstrated that STAT3 is a direct target of miR-1301. Gain and loss-of-function assays showed that miR-1301 had no effect on cell proliferation. Overexpression of miR-1301 suppressed cell migration and invasion capacity of pSTA3-positive LoVo cells, but not pSTAT3-negative SW480 cells, while inhibition of miR-1301 consistently promoted cell migration and invasion in both cell lines. Additionally, miR-1301 inhibition restored the suppressed migration and invasion of STAT3- knockdown LoVo cells. MiR-1301 functioned as a tumor suppressor to modulate the IL6/STAT3 signaling pathway. In summary, this study highlights the significant role of miR- 1301/STAT3 axis in CRC metastasis.

scholarly journals RIP140 Represses Intestinal Paneth Cell Differentiation and Interplays with SOX9 Signaling in Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3192
Author(s):  
Antoine Gleizes ◽  
Mouna Triki ◽  
Sandrine Bonnet ◽  
Naomi Baccari ◽  
Gabriel Jimenez-Dominguez ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Differentiation ◽  
Paneth Cell ◽  
Wnt Signaling Pathway ◽  
Cell Lineage ◽  
Human Colon ◽  
Luciferase Reporter ◽  
Loss Of Function ◽  
Sox9 Expression ◽  
Human Colon Cancer

RIP140 is a major transcriptional coregulator of gut homeostasis and tumorigenesis through the regulation of Wnt/APC signaling. Here, we investigated the effect of RIP140 on Paneth cell differentiation and its interplay with the transcription factor SOX9. Using loss of function mouse models, human colon cancer cells, and tumor microarray data sets we evaluated the role of RIP140 in SOX9 expression and activity using RT-qPCR, immunohistochemistry, luciferase reporter assays, and GST-pull down. We first evidence that RIP140 strongly represses the Paneth cell lineage in the intestinal epithelium cells by inhibiting Sox9 expression. We then demonstrate that RIP140 interacts with SOX9 and inhibits its transcriptional activity. Our results reveal that the Wnt signaling pathway exerts an opposite regulation on SOX9 and RIP140. Finally, the levels of expression of RIP140 and SOX9 exhibit a reverse response and prognosis value in human colorectal cancer biopsies. This work highlights an intimate transcriptional cross-talk between RIP140 and SOX9 in intestinal physiopathology.

scholarly journals Long noncoding RNA FER1L4 promotes the malignant processes of papillary thyroid cancer by targeting the miR-612/ Cadherin 4 axis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Luyao Wu ◽  
Yu Ding ◽  
Houchao Tong ◽  
Xi Zhuang ◽  
Jingsheng Cai ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Noncoding Rna ◽  
Animal Experiments ◽  
Ectopic Expression ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Papillary Thyroid ◽  
Loss Of Function ◽  
Functional Roles

Abstract Background Long noncoding RNAs (lncRNAs) have emerged as crucial regulators in various cancers. However, the functional roles of most lncRNA in papillary thyroid cancer (PTC) are not detailly understood. This study aims to investigate the biological function and molecular mechanism of lncRNA Fer-1 like family member 4 (FER1L4) in PTC. Methods The expression of FER1L4 in PTC was determined via operating quantitative real-time PCR assays. Meanwhile, the clinical significance of FER1L4 in patients with PTC was described. The biological functions of FER1L4 on PTC cells were evaluated by gain and loss of function experiments. Moreover, animal experiments were performed to reveal the effect on tumor growth. Subcellular distribution of FER1L4 was determined by fluorescence in situ hybridization and subcellular localization assays. Luciferase reporter assay and RNA immunoprecipitation assay were applied to define the relationship between FER1L4, miR-612, and Cadherin 4 (CDH4). Results Upregulated expression of FER1L4 in PTC tissues was positively correlated with lymph node metastasis (P = 0.020), extrathyroidal extension (P = 0.013) and advanced TNM stages (P = 0.013). In addition, knockdown of FER1L4 suppressed PTC cell proliferation, migration, and invasion, whereas ectopic expression of FER1L4 inversely promoted these processes. Mechanistically, FER1L4 could competitively bind with miR-612 to prevent the degradation of its target gene CDH4. This condition was further confirmed in the rescue assays. Conclusions This study first demonstrates FER1L4 plays an oncogenic role in PTC via a FER1L4-miR-612-CDH4 axis and may provide new therapeutic and diagnostic targets for PTC.

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