scholarly journals Extracellular vesicles-derived microRNA-222 promotes immune escape via interacting with ATF3 to regulate AKT1 transcription in colorectal cancer

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Shiquan Li ◽  
Guoqiang Yan ◽  
Meng Yue ◽  
Lei Wang
Keyword(s):  
Colorectal Cancer ◽  
Extracellular Vesicles ◽  
Posttranscriptional Regulation ◽  
Target Genes ◽  
Immune Escape ◽  
Cell Activity ◽  
Akt Pathway ◽  
Before And After

Abstract Background Immunotherapy has been recently established as a new direction for the treatment of colorectal cancer (CRC), a gastrointestinal cancer. In this investigation, we aimed to expound how the posttranscriptional regulation modulated by microRNA-222 (miR-222) from mesenchymal stem cells-derived extracellular vesicles (MSC-EVs) affected the AKT pathway and the immune escape in CRC. Methods CRC cell malignant phenotype, including proliferation, migration, invasion, and apoptosis, was firstly detected after co-culture with MSC-EVs. miRNAs with differential changes in CRC cells before and after EVs treatment were filtered by microarray analysis. miR-222 was then downregulated to examine its role in CRC cells in response to EVs. Cells were implanted in mice to induce xenograft tumors, and infiltrating T cells was assessed by immunohistochemistry. The mRNA microarray was used to screen target genes, followed by rescue experiments. ChIP and western blot were conducted to validate the downstream biomolecule of ATF3. Results After treatment of CRC cells with MSC-EVs, the expression of miR-222 was upregulated, and cell activity was increased. Inhibition of miR-222 decreased CRC malignant aggressiveness in vitro and reduced tumorigenesis and immune escape in vivo. miR-222 targeted and bound to ATF3. Downregulation of ATF3 enhanced CRC cell malignant aggressiveness, tumorigenic capacity and immune escape. Mechanistically, ATF3 inhibited AKT1 transcription and mediated the AKT pathway. Conclusion MSC-EVs carry miR-222 to promote CRC cell malignant aggressiveness and immune escape. miR-222 targets and binds to ATF3, which inhibits AKT1 transcriptional activity and thereby mediates the AKT pathway.

PGM1 Suppresses Colorectal Cancer Cell Migration And Invasion by Regulating PI3K/ AKT Pathway

2021 ◽  
Author(s):  
Zhewen Zheng ◽  
Xue Zhang ◽  
Jian Bai ◽  
Long Long ◽  
Di Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Colony Formation ◽  
Tumor Formation ◽  
Akt Pathway ◽  
Migration And Invasion ◽  
Cycle Arrest ◽  
Cancer Pathogenesis

Abstract BackgroundPhosphoglucomutase 1(PGM1) is known for its involvement in cancer pathogenesis. However, its biological role in colorectal cancer (CRC) is unknown. Here, we studied the functions and mechanisms of PGM1 in CRC.Methods We verified PGM-1 as a DEG by a comprehensive strategy of the TCGA-COAD dataset mining and computational biology. Relative levels of PGM-1 in CRC tumors and adjoining peritumoral tissue were identified by qRT-PCR, WB, and IHC staining in a tissue microarray. PGM1 functions were analyzed using CCK8, EdU, colony formation, cell cycle, apoptosis, and Transwell migration and invasion assays. The influence of PGM1 was further investigated using tumor formation in vivo.ResultsPGM1 mRNA and protein were both reduced in CRC and the reduction was related to CRC pathology and overall survival. PGM1 knockdown stimulated both proliferation and colony formation, promoting cell cycle arrest and apoptosis while overexpression has opposite effects in CRC cells both in vivo and in vitro. Furthermore, we lined the actions of PGM1 to the PI3K/ AKT pathway. ConclusionWe verified that PGM1 suppresses CRC through the PI3K/ AKT pathway. These results suggest the potential for targeting PGM1 in CRC therapies.

scholarly journals MACC1 Suppresses Cell Apoptosis in Hepatocellular Carcinoma by Targeting the HGF/c-MET/AKT Pathway

2015 ◽  
Vol 35 (3) ◽  
pp. 983-996 ◽  
Author(s):  
Yingmin Yao ◽  
Chanwei Dou ◽  
Zhongtang Lu ◽  
Xin Zheng ◽  
Qingguang Liu
Keyword(s):  
Cell Apoptosis ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Annexin V ◽  
Akt Pathway ◽  
Caspase 9 ◽  
Dapi Staining ◽  
In Vivo Experiments

Background & Aims: To investigate the expression and prognostic value of MACC1 in patients with HCC and identify the mechanism by which MACC1 inhibits HCC cell apoptosis. Methods: MACC1 and p-AKT expression was studied using immunohistochemistry of both HCC tissues and adjacent liver tissues. qRT-PCR and western immunoblotting were used to examine the expression of target genes at the mRNA and protein levels, respectively. The MTT assay was used to assess cell viability, and cell apoptosis was determined by DAPI staining, Annexin V/PI staining and Caspase 3/7 assay. Nude mice were used to perform in vivo experiments. Results: The overexpression of MACC1 was found in HCC tissues and was correlated with poor postsurgical prognosis. There was a positive relationship between MACC1 and p-AKT expression in HCC tissues. In vitro experiments showed that MACC1 repressed HCC cell apoptosis and promoted cell growth. Knockdown of c-MET abolished the anti-apoptotic function of MACC1. Next, MACC1 was verified to activate PI3K/AKT signaling by sensitizing HGF/c-MET signaling in HCC. MACC1 overexpression enhanced the HGF-driven phosphorylation of BAD, Caspase 9 and FKHRL1 and inhibited their pro-apoptotic functions in HCC cells. Finally, MACC1 was shown to inhibit cell apoptosis and promote HCC growth in vivo. Conclusions: This investigation revealed that MACC1 overexpression predicted worse prognosis after liver resection, which was attributed to the repression of HCC cell apoptosis via a molecular mechanism in which MACC1 accelerated the activation of the HGF/c-MET/PI3K/AKT pathway and phosphorylated BAD, Caspase 9 and FKHRL1, ultimately preventing their nuclear translocation and their pro-apoptotic function.

scholarly journals Uterine progesterone signaling is a target for metformin therapy in PCOS-like rats

2018 ◽  
Vol 237 (2) ◽  
pp. 123-137 ◽  
Author(s):  
Min Hu ◽  
Yuehui Zhang ◽  
Jiaxing Feng ◽  
Xue Xu ◽  
Jiao Zhang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Target Genes ◽  
Polycystic Ovary ◽  
Metformin Therapy ◽  
Before And After ◽  
Elevated Expression ◽  
Targeted Gene Expression ◽  
First Time

Impaired progesterone (P4) signaling is linked to endometrial dysfunction and infertility in women with polycystic ovary syndrome (PCOS). Here, we report for the first time that elevated expression of progesterone receptor (PGR) isoforms A and B parallels increased estrogen receptor (ER) expression in PCOS-like rat uteri. The aberrant PGR-targeted gene expression in PCOS-like rats before and after implantation overlaps with dysregulated expression of Fkbp52 and Ncoa2, two genes that contribute to the development of uterine P4 resistance. In vivo and in vitro studies of the effects of metformin on the regulation of the uterine P4 signaling pathway under PCOS conditions showed that metformin directly inhibits the expression of PGR and ER along with the regulation of several genes that are targeted dependently or independently of PGR-mediated uterine implantation. Functionally, metformin treatment corrected the abnormal expression of cell-specific PGR and ER and some PGR-target genes in PCOS-like rats with implantation. Additionally, we documented how metformin contributes to the regulation of the PGR-associated MAPK/ERK/p38 signaling pathway in the PCOS-like rat uterus. Our data provide novel insights into how metformin therapy regulates uterine P4 signaling molecules under PCOS conditions.

scholarly journals Jujuboside B induces mitochondrial-dependent apoptosis in colorectal cancer through ROS-mediated PI3K/Akt pathway in vitro and in vivo

2021 ◽  
Vol 87 ◽  
pp. 104796
Author(s):  
Xiaoling Li ◽  
Meicui Chen ◽  
Zhicui Yao ◽  
Hongzhen Du ◽  
Tianfeng Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Akt Pathway

scholarly journals Uterine progesterone signaling is a target for metformin therapy in PCOS-like rats

2017 ◽  
Author(s):  
Min Hu ◽  
Yuehui Zhang ◽  
Jiaxing Feng ◽  
Xue Xu ◽  
Jiao Zhang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Target Genes ◽  
Polycystic Ovary ◽  
Metformin Therapy ◽  
Before And After ◽  
Elevated Expression ◽  
Targeted Gene Expression ◽  
First Time

AbstractImpaired progesterone (P4) signaling is linked to endometrial dysfunction and infertility in women with polycystic ovary syndrome (PCOS). Here we report for the first time that elevated expression of progesterone receptor (PGR) isoforms A and B parallels increased estrogen receptor (ER) expression in PCOS-like rat uteri. The aberrant PGR-targeted gene expression in PCOS-like rats before and after implantation overlaps with dysregulated expression of Fkbp52 and Ncoa2, two genes that contribute to the development of uterine P4 resistance. In vivo and in vitro studies of the effects of metformin on the regulation of the uterine P4 signaling pathway under PCOS conditions showed that metformin directly inhibits the expression of PGR and ER along with the regulation of several genes that are targeted dependently or independently of PGR-mediated uterine implantation. Functionally, metformin treatment corrected the abnormal expression of cell-specific PGR and ER and some PGR-target genes in PCOS-like rats with implantation. Additionally, we documented how metformin contributes to the regulation of the PGR-associated MAPK/ERK/p38 signaling pathway in the PCOS-like rat uterus. Our data provide novel insights into how metformin therapy regulates uterine P4 signaling molecules under PCOS conditions.

scholarly journals miR-125b Promotes Colorectal Cancer Migration and Invasion by Dual-Targeting CFTR and CGN

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5710
Author(s):  
Xiaohui Zhang ◽  
Tingyu Li ◽  
Ya-Nan Han ◽  
Minghui Ge ◽  
Pei Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Rho Kinase ◽  
Causative Factor ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Metastasis contributes to the poor prognosis of colorectal cancer, the causative factor of which is not fully understood. Previously, we found that miR-125b (Accession number: MIMAT0000423) contributed to cetuximab resistance in colorectal cancer (CRC). In this study, we identified a novel mechanism by which miR-125b enhances metastasis by targeting cystic fibrosis transmembrane conductance regulator (CFTR) and the tight junction-associated adaptor cingulin (CGN) in CRC. We found that miR-125b expression was upregulated in primary CRC tumors and metastatic sites compared with adjacent normal tissues. Overexpression of miR-125b in CRC cells enhanced migration capacity, while knockdown of miR-125b decreased migration and invasion. RNA-sequencing (RNA-seq) and dual-luciferase reporter assays identified CFTR and CGN as the target genes of miR-125b, and the inhibitory impact of CFTR and CGN on metastasis was further verified both in vitro and in vivo. Moreover, we found that miR-125b facilitated the epithelial-mesenchymal transition (EMT) process and the expression and secretion of urokinase plasminogen activator (uPA) by targeting CFTR and enhanced the Ras Homolog Family Member A (RhoA)/Rho Kinase (ROCK) pathway activity by targeting CGN. Together, these findings suggest miR-125b as a key functional molecule in CRC and a promising biomarker for the diagnosis and treatment of CRC.

scholarly journals The LncRNA CASC11 Promotes Colorectal Cancer Cell Proliferation and Migration by Adsorbing miR-646 and miR-381-3p to Upregulate Their Target RAB11FIP2

2021 ◽  
Vol 11 ◽  
Author(s):  
Wei Zhang ◽  
Xiaomin Li ◽  
Wenjuan Zhang ◽  
Yanxia Lu ◽  
Weihao Lin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Target Genes ◽  
Suppressive Effect ◽  
Luciferase Reporter ◽  
Expression Levels ◽  
Non Coding Rna ◽  
Potential Biomarker ◽  
And Migration

BackgroundWe previously reported that the long non-coding RNA (lncRNA) CASC11 promotes colorectal cancer (CRC) progression as an oncogene by binding to HNRNPK. However, it remains unknown whether CASC11 can act as a competitive endogenous RNA (ceRNA) in CRC. In this study, we focused on the role of CASC11 as a ceRNA in CRC by regulating miR-646 and miR-381-3p targeting of RAB11FIP2.MethodsWe identified the target microRNAs (miRNAs) of CASC11 and the target genes of miR-646 and miR-381-3p using bioinformatic methods. A dual-luciferase reporter assay was performed to validate the target relationship. Quantitative real-time PCR (qRT-PCR), western blotting (WB), and immunohistochemistry (IHC) were used to measure the RNA and protein expression levels. Rescue experiments in vitro and in vivo were performed to investigate the influence of the CASC11/miR-646 and miR-381-3p/RAB11FIP2 axis on CRC progression.ResultsWe found that CASC11 binds to miR-646 and miR-381-3p in the cytoplasm of CRC cells. Moreover, miR-646 and miR-381-3p inhibitors reversed the suppressive effect of CASC11 silencing on CRC growth and metastasis in vitro and in vivo. We further confirmed that RAB11FIP2 is a mutual target of miR-646 and miR-381-3p. The expression levels of CASC11 and RAB11FIP2 in CRC were positively correlated and reciprocally regulated. Further study showed that CASC11 played an important role in regulating PI3K/AKT pathway by miR-646 and miR-381-3p/RAB11FIP2 axis.ConclusionOur study showed that CASC11 promotes the progression of CRC as a ceRNA by sponging miR-646 and miR-381-3p. Thus, CASC11 is a potential biomarker and a therapeutic target of CRC.

scholarly journals Physiological Significance of Reactive Cysteine Residues of Keap1 in Determining Nrf2 Activity

2008 ◽  
Vol 28 (8) ◽  
pp. 2758-2770 ◽  
Author(s):  
Tae Yamamoto ◽  
Takafumi Suzuki ◽  
Akira Kobayashi ◽  
Junko Wakabayashi ◽  
Jon Maher ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Target Genes ◽  
Cysteine Residue ◽  
Cysteine Residues ◽  
Transgenic Expression ◽  
Ubiquitin E3 Ligase ◽  
Nrf2 Activation ◽  
Before And After

ABSTRACT Keap1 and Cul3 constitute a unique ubiquitin E3 ligase that degrades Nrf2, a key activator of cytoprotective genes. Upon exposure to oxidants/electrophiles, the enzymatic activity of this ligase complex is inhibited and the complex fails to degrade Nrf2, resulting in the transcriptional activation of Nrf2 target genes. Keap1 possesses several reactive cysteine residues that covalently bond with electrophiles in vitro. To clarify the functional significance of each Keap1 cysteine residue under physiological conditions, we established a transgenic complementation rescue model. The transgenic expression of mutant Keap1(C273A) and/or Keap1(C288A) protein in Keap1 null mice failed to reverse constitutive Nrf2 activation, indicating that cysteine residues at positions 273 and 288 are essential for Keap1 to repress Nrf2 activity in vivo. In contrast, Keap1(C151S) retained repressor activity and mice expressing this molecule were viable. Mouse embryonic fibroblasts from Keap1(C151S) transgenic mice displayed decreased expression of Nrf2 target genes both before and after an electrophilic challenge, suggesting that Cys151 is important in facilitating Nrf2 activation. These results demonstrate critical roles of the cysteine residues in vivo in maintaining Keap1 function, such that Nrf2 is repressed under quiescent conditions and active in response to oxidants/electrophiles.

scholarly journals B7-H3 regulates KIF15-activated ERK1/2 pathway and contributes to radioresistance in colorectal cancer

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Yanchao Ma ◽  
Shenghua Zhan ◽  
Huimin Lu ◽  
Ruoqin Wang ◽  
Yunyun Xu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Radiation Treatment ◽  
Costimulatory Molecule ◽  
Cell Activity ◽  
Alternative Mechanism ◽  
Neoadjuvant Radiotherapy ◽  
Normal Tissues ◽  
Enhanced Expression

Abstract As an important modality for the local control of colorectal cancer (CRC), radiotherapy or neoadjuvant radiotherapy is widely applied in the clinic, but radioresistance has become a major obstacle for CRC radiotherapy. Here we reported that B7-H3, an important costimulatory molecule, is associated with radioresistance in CRC. The expression of B7-H3 was obviously increased in CRC cells after irradiation. The enhanced expression of B7-H3 promoted, while the knockdown of B7-H3 inhibited, colony formation and cell activity in CRC cells following radiation treatment. B7-H3 overexpression reduced S phase arrest and protected cell apoptosis induced by radiation, whereas B7-H3 knockdown had the opposite effects. In addition, B7-H3 blockade by 3E8, a specific B7-H3 antibody, significantly sensitized CRC cells to irradiation in vivo. Mechanistic analysis revealed that B7-H3 regulated KIF15 via RNA sequencing, which was in dependent of NF-κB pathway. And small interfering RNA (siRNA)-mediated KIF15 silencing or KIF15 blockade by the inhibitor SB743921 abolished the effect of B7-H3 on radioresistance in vitro and in vivo. Similar to B7-H3, we find that the protein expression levels of KIF15, which showed a positive correlation with B7-H3, was abnormal upregulated in cancer tissues than in adjacent normal tissues and associated with TNM stage. Finally, B7-H3/KIF15 enhanced resistance against irradiation in CRC cells via activating ERK1/2 signaling, a key pathway involved in radioresistance in cancer. Our findings reveal an alternative mechanism by which CRC cells can acquire radioresistance via the B7-H3/KIF15/ERK axis.

Sign in / Sign up

Export Citation Format

Share Document