scholarly journals Tumor-associated macrophages (TAMs) depend on MMP1 for their cancer-promoting role

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Junhui Yu ◽  
Zhengshui Xu ◽  
Jing Guo ◽  
Kui Yang ◽  
Jianbao Zheng ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Cyclin B1 ◽  
Cancer Cell Proliferation ◽  
Tumor Associated Macrophages ◽  
M Phase ◽  
Cell Cycle Transition

AbstractThe complex interaction between tumor-associated macrophages (TAMs) and tumor cells through several soluble factors and signaling is essential for colorectal cancer (CRC) progression. However, the molecular mechanism involved remains elusive. In this study, we demonstrated that MMP1 derived from TAMs markedly facilitated colon cancer cell proliferation via accelerating cell cycle transition from G0/G1 to S and G2/M phase. Moreover, exogenous MMP1 activated cdc25a/CDK4-cyclin D1 and p21/cdc2-cyclin B1 complexes through altering c-Myc and ETV4. Mechanistic studies indicated that inhibition of PAR1 or blockage of MAPK/Erk signaling eliminated the proliferation induced by exogenous MMP1 in vitro and in vivo. In addition, ETV4 could bind to the promoter of MMP1 and activate MMP1 transcription, which confirmed the MMP1/ETV4/MMP1 positive feedback. Altogether, our study identified a cytokine paracrine manner between colon cancer cells and TAMs. MMP1/PAR1/Erk1/2/ETV4 positive feedback loop may represent to be a therapeutic target and prognostic marker in CRC.

scholarly journals LncRNA MIR17HG promotes colorectal cancer liver metastasis by mediating a glycolysis-associated positive feedback circuit

Oncogene ◽  
2021 ◽  
Author(s):  
Senlin Zhao ◽  
Bingjie Guan ◽  
Yushuai Mi ◽  
Debing Shi ◽  
Ping Wei ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Metastatic Tumor ◽  
Feedback Circuit ◽  
Colorectal Cancer Liver Metastasis ◽  
Positive Feedback Circuit

AbstractGlycolysis plays a crucial role in reprogramming the metastatic tumor microenvironment. A series of lncRNAs have been identified to function as oncogenic molecules by regulating glycolysis. However, the roles of glycolysis-related lncRNAs in regulating colorectal cancer liver metastasis (CRLM) remain poorly understood. In the present study, the expression of the glycolysis-related lncRNA MIR17HG gradually increased from adjacent normal to CRC to the paired liver metastatic tissues, and high MIR17HG expression predicted poor survival, especially in patients with liver metastasis. Functionally, MIR17HG promoted glycolysis in CRC cells and enhanced their invasion and liver metastasis in vitro and in vivo. Mechanistically, MIR17HG functioned as a ceRNA to regulate HK1 expression by sponging miR-138-5p, resulting in glycolysis in CRC cells and leading to their invasion and liver metastasis. More interestingly, lactate accumulated via glycolysis activated the p38/Elk-1 signaling pathway to promote the transcriptional expression of MIR17HG in CRC cells, forming a positive feedback loop, which eventually resulted in persistent glycolysis and the invasion and liver metastasis of CRC cells. In conclusion, the present study indicates that the lactate-responsive lncRNA MIR17HG, acting as a ceRNA, promotes CRLM through a glycolysis-mediated positive feedback circuit and might be a novel biomarker and therapeutic target for CRLM.

scholarly journals CDK13 upregulation-induced formation of the positive feedback loop among circCDK13, miR-212-5p/miR-449a and E2F5 contributes to prostate carcinogenesis

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Jin-Chun Qi ◽  
Zhan Yang ◽  
Tao Lin ◽  
Long Ma ◽  
Ya-Xuan Wang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Transcriptional Activation ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Biological Effects ◽  
Therapeutic Benefit ◽  
Loss Of Function ◽  
Positive Feedback Loop

Abstract Background Both E2F transcription factor and cyclin-dependent kinases (CDKs), which increase or decrease E2F activity by phosphorylating E2F or its partner, are involved in the control of cell proliferation, and some circRNAs and miRNAs regulate the expression of E2F and CDKs. However, little is known about whether dysregulation among E2Fs, CDKs, circRNAs and miRNAs occurs in human PCa. Methods The expression levels of CDK13 in PCa tissues and different cell lines were determined by quantitative real-time PCR and Western blot analysis. In vitro and in vivo assays were preformed to explore the biological effects of CDK13 in PCa cells. Co-immunoprecipitation anlysis coupled with mass spectrometry was used to identify E2F5 interaction with CDK13. A CRISPR-Cas9 complex was used to activate endogenous CDK13 and circCDK13 expression. Furthermore, the mechanism of circCDK13 was investigated by using loss-of-function and gain-of-function assays in vitro and in vivo. Results Here we show that CDK13 is significantly upregulated in human PCa tissues. CDK13 depletion and overexpression in PCa cells decrease and increase, respectively, cell proliferation, and the pro-proliferation effect of CDK13 is strengthened by its interaction with E2F5. Mechanistically, transcriptional activation of endogenous CDK13, but not the forced expression of CDK13 by its expression vector, remarkably promotes E2F5 protein expression by facilitating circCDK13 formation. Further, the upregulation of E2F5 enhances CDK13 transcription and promotes circCDK13 biogenesis, which in turn sponges miR-212-5p/449a and thus relieves their repression of the E2F5 expression, subsequently leading to the upregulation of E2F5 expression and PCa cell proliferation. Conclusions These findings suggest that CDK13 upregulation-induced formation of the positive feedback loop among circCDK13, miR-212-5p/miR-449a and E2F5 is responsible for PCa development. Targeting this newly identified regulatory axis may provide therapeutic benefit against PCa progression and drug resistance.

scholarly journals Interaction of Apoptotic Cells with Macrophages Upregulates COX-2/PGE2and HGF Expression via a Positive Feedback Loop

2014 ◽  
Vol 2014 ◽  
pp. 1-17 ◽  
Author(s):  
Ji Yeon Byun ◽  
Young-So Youn ◽  
Ye-Ji Lee ◽  
Youn-Hee Choi ◽  
So-Yeon Woo ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Tissue Repair ◽  
Feedback Loop ◽  
Apoptotic Cell ◽  
Raw 264.7 Cells ◽  
Apoptotic Cells ◽  
Positive Feedback Loop ◽  
Cox 2

Recognition of apoptotic cells by macrophages is crucial for resolution of inflammation, immune tolerance, and tissue repair. Cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) and hepatocyte growth factor (HGF) play important roles in the tissue repair process. We investigated the characteristics of macrophage COX-2 and PGE2expression mediated by apoptotic cells and then determined how macrophages exposed to apoptotic cellsin vitroandin vivoorchestrate the interaction between COX-2/PGE2and HGF signaling pathways. Exposure of RAW 264.7 cells and primary peritoneal macrophages to apoptotic cells resulted in induction of COX-2 and PGE2. The COX-2 inhibitor NS-398 suppressed apoptotic cell-induced PGE2production. Both NS-398 and COX-2-siRNA, as well as the PGE2receptor EP2 antagonist, blocked HGF expression in response to apoptotic cells. In addition, the HGF receptor antagonist suppressed increases in COX-2 and PGE2induction. Thein vivorelevance of the interaction between the COX-2/PGE2and HGF pathways through a positive feedback loop was shown in cultured alveolar macrophages followingin vivoexposure of bleomycin-stimulated lungs to apoptotic cells. Our results demonstrate that upregulation of the COX-2/PGE2and HGF in macrophages following exposure to apoptotic cells represents a mechanism for mediating the anti-inflammatory and antifibrotic consequences of apoptotic cell recognition.

scholarly journals A Positive Feedback Loop of lncRNA MIR31HG-miR-361-3p -YY1 Accelerates Colorectal Cancer Progression Through Modulating Proliferation, Angiogenesis, and Glycolysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Tao Guo ◽  
Defeng Liu ◽  
Shihao Peng ◽  
Meng Wang ◽  
Yangyang Li
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Luciferase Reporter ◽  
Loss Of Function ◽  
Positive Feedback Loop ◽  
Related Proteins

BackgroundColorectal cancer (CRC) is a common malignant tumor with high metastatic and recurrent rates. This study probes the effect and mechanism of long non-coding RNA MIR31HG on the progression of CRC cells.Materials and MethodsQuantitative real-time PCR (qRT-PCR) was used to analyze the expression of MIR31HG and miR-361-3p in CRC tissues and normal tissues. Gain- or loss-of-function assays were conducted to examine the roles of MIR31HG, miR-361-3p and YY1 transcription factor (YY1) in the CRC progression. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and colony formation experiment were conducted to test CRC cell proliferation. CRC cell invasion was determined by Transwell assay. The glucose detection kit and lactic acid detection kit were utilized to monitor the levels of glucose and lactate in CRC cells. The glycolysis level in CRC cells was examined by the glycolytic stress experiment. Western blot was performed to compare the expression of glycolysis-related proteins (PKM2, GLUT1 and HK2) and angiogenesis-related proteins (including VEGFA, ANGPT1, HIF1A and TIMP1) in HUVECs. The binding relationships between MIR31HG and miR-361-3p, miR-361-3p and YY1 were evaluated by the dual-luciferase reporter assay and RNA immunoprecipitation (RIP).ResultsMIR31HG was up-regulated in CRC tissues and was associated with poorer prognosis of CRC patients. The in-vitro and in-vivo experiments confirmed that overexpressing MIR31HG heightened the proliferation, growth, invasion, glycolysis and lung metastasis of CRC cells as well as the angiogenesis of HUVECs. In addition, MIR3HG overexpression promoted YY1 mRNA and protein level, and forced overexpression of YY1 enhanced MIR31HG level. Overexpressing YY1 reversed the tumor-suppressive effect mediated by MIR31HG knockdown. miR-361-3p, which was inhibited by MIR31HG overexpression, repressed the malignant behaviors of CRC cells. miR-361-3p-mediated anti-tumor effects were mostly reversed by upregulating MIR31HG. Further mechanism studies illustrated that miR-361-3p targeted and negatively regulated the expression of YY1.ConclusionThis study reveals that MIR31HG functions as an oncogenic gene in CRC via forming a positive feedback loop of MIR31HG-miR-361-3p-YY1.

Protein kinase D inhibitor CRT0066101 suppresses bladder cancer growth in vitro and in vivo through induction of cell cycle arrest at the G2-M phase.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16024-e16024
Author(s):  
Qingdi Quentin Li ◽  
Iawen Hsu ◽  
Thomas Sanford ◽  
Reema S. Railkar ◽  
Piyush K. Agarwal
Keyword(s):  
Cell Cycle ◽  
Flow Cytometry ◽  
Bladder Cancer ◽  
Cyclin B1 ◽  
Cancer Growth ◽  
Protein Kinase D ◽  
Bladder Cancer Cells ◽  
M Phase

e16024 Background: Protein Kinase D (PKD) is implicated in tumor growth, death, invasion, and progression. CRT0066101 is an inhibitor of PKD and has antitumor activity in several types of carcinomas. However, the effect and mechanism of CRT0066101 in bladder cancer remain unknown. Methods: The MTS assay was used to evaluate the ability of CRT0066101 to inhibit cellular proliferation in bladder cancer cells. Cell cycle was analyzed by flow cytometry. Protein expression and phosphorylation were assessed by western blotting. Results: We showed that CRT0066101 suppressed the proliferation and migration of 4 bladder cancer cell lines in vitro. We also demonstrated that CRT0066101 inhibited tumor growth in an in vivo mouse model of bladder cancer. To verify the role of PKD in bladder tumor, we found that PKD2 was highly expressed in 8 bladder cancer lines and that RNA interference-mediated silencing of the PKD2 gene dramatically reduced bladder cancer growth in vitro and in vivo, suggesting that the effect of the compound in bladder cancer is mediated through inhibition of PKD2. This notion was confirmed by demonstrating that the levels of PKD2 and phospho-PKD2 (Ser-876) were markedly decreased in CRT0066101-treated bladder cancer. In addition, our cell cycle analysis by flow cytometry revealed that CRT0066101 arrested bladder cancer cells at the G2-M phase. We further validated these data by immunoblotting showing that treatment of bladder carcinoma cells with CRT0066101 downregulated the expression of cyclin B1, cdc2 and cdc25C, but elevated the levels of p27kip1, gadd45a, chk1/2, and wee1. Finally, CRT0066101 was found to increase the phosphorylation of cdc2 and cdc25C, which lead to reduction in cdc2-cyclin B1 activity. Conclusions: These novel findings suggest that CRT0066101 inhibits bladder cancer growth through modulating the cell cycle G2 checkpoint and inducing cell cycle G2-M arrest, which lead to blockade of cell cycle progression. QQL and IH contributed equally to this work.

scholarly journals S-Allylmercaptocysteine induces G2/M phase arrest and apoptosis via ROS-mediated p38 and JNK signaling pathway in human colon cancer cells in vitro and in vivo

RSC Advances ◽  
2017 ◽  
Vol 7 (77) ◽  
pp. 49151-49158 ◽  
Author(s):  
Xiaosong Zhu ◽  
Xiaoyan Jiang ◽  
Chonggang Duan ◽  
Ang Li ◽  
Yueyue Sun ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Human Colon ◽  
Cancer Cell Growth ◽  
Human Colon Cancer ◽  
M Phase ◽  
Jnk Signaling Pathway ◽  
Human Colon Cancer Cells ◽  
Dependent Pathway

SAMC inhibits colon cancer cell growth through the reactive oxygen species-dependent pathway.

scholarly journals Long Noncoding RNA HCG18 Promotes Malignant Phenotypes of Breast Cancer Cells via the HCG18/miR-103a-3p/UBE2O/mTORC1/HIF-1α–Positive Feedback Loop

2021 ◽  
Vol 9 ◽  
Author(s):  
Xu Liu ◽  
Kun Qiao ◽  
Kaiyuan Zhu ◽  
Xianglan Li ◽  
Chunbo Zhao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Positive Feedback ◽  
Noncoding Rna ◽  
Feedback Loop ◽  
Hypoxia Inducible Factor ◽  
The Cancer Genome Atlas ◽  
Positive Feedback Loop ◽  
Downstream Target

In recent years, an increasing number of studies have reported that long noncoding RNAs (lncRNAs) play crucial roles in breast cancer (BC) progression and metastasis. Another study group of our research center reported that lncRNA HCG18 was one of the 30 upregulated lncRNAs in BC tissues compared with normal tissues in The Cancer Genome Atlas database. However, the exact biological roles of HCG18 in BC remain unclear. In this study, we demonstrated that HCG18 is significantly upregulated in BC tissues and cells and that BC patients with high HCG18 expression tend to have poor prognosis. In vitro assays indicated that HCG18 promotes BC cell proliferation and invasion and endows BC cells with cancer stemness properties. In vivo assays revealed that reducing HCG18 expression in the BC cell line MDA-MB-231 markedly decreased tumor growth and lung metastasis in xenograft mouse models. In terms of mechanism, we found that HCG18 positively regulated the expression of BC-related ubiquitin-conjugating enzyme E2O (UBE2O) by sponging miR-103a-3p, and our previous research verified that UBE2O could promote the malignant phenotypes of BC cells through the UBE2O/AMPKα2/mTORC1 axis. Furthermore, as a downstream target of the HCG18/miR-103a-3p/UBE2O/mTORC1 axis, hypoxia-inducible factor 1α transcriptionally promoted HCG18 expression and then formed a positive feedback loop in BC. Taken together, these results confirm that HCG18 plays an oncogenic role in BC and might serve as a prognostic biomarker and a potential therapeutic target for BC treatment.

scholarly journals DNMT1-induced miR-378a-3p silencing promotes angiogenesis via the NF-κB signaling pathway by targeting TRAF1 in hepatocellular carcinoma

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Bin Zhu ◽  
Jun-Jie Chen ◽  
Ying Feng ◽  
Jun-Ling Yang ◽  
Hua Huang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Positive Feedback ◽  
Dna Methyltransferase ◽  
Feedback Loop ◽  
Tube Formation ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Positive Feedback Loop

Abstract Background Angiogenesis plays an important role in the occurrence, development and metastasis of hepatocellular carcinoma (HCC). According to previous studies, miR-378a participates in tumorigenesis and tumor metastasis, but its exact role in HCC angiogenesis remains poorly understood. Methods qRT-PCR was used to investigate the expression of miR-378a-3p in HCC tissues and cell lines. The effects of miR-378a-3p on HCC in vitro and in vivo were examined by Cell Counting Kit-8 (CCK-8), Transwell, tube formation and Matrigel plug assays, RNA sequencing, bioinformatics, luciferase reporter, immunofluorescence and chromatin immunoprecipitation (ChIP) assays were used to detect the molecular mechanism by which miR-378a-3p inhibits angiogenesis. Results We confirmed that miR-378a-3p expression was significantly downregulated and associated with higher microvascular density (MVD) in HCC; miR-378a-3p downregulation indicated a short survival time in HCC patients. miR-378a-3p knockdown led to a significant increase in angiogenesis in vitro and in vivo. We found that miR-378a-3p directly targeted TNF receptor associated factor 1 (TRAF1) to attenuate NF-κB signaling, and then downregulated secreted vascular endothelial growth factor. DNA methyltransferase 1 (DNMT1)-mediated hypermethylation of miR-378a-3p was responsible for downregulating miR-378a-3p. Moreover, a series of investigations indicated that p65 initiated a positive feedback loop that could upregulate DNMT1 to promote hypermethylation of the miR-378a-3p promoter. Conclusion Our study indicates a novel DNMT1/miR-378a-3p/TRAF1/NF-κB positive feedback loop in HCC cells, which may become a potential therapeutic target for HCC.

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