scholarly journals CPEB3 inhibits epithelial-mesenchymal transition by disrupting the crosstalk between colorectal cancer cells and tumor-associated macrophages via IL-6R/STAT3 signaling

2020 ◽  
Author(s):  
Qian Zhong ◽  
Yuxin Fang ◽  
Qiuhua Lai ◽  
Shanci Wang ◽  
Chengcheng He ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Macrophage Polarization ◽  
Tumor Associated Macrophages ◽  
Antibody Treatment ◽  
Mesenchymal Transition ◽  
Stat3 Signaling

Abstract Background: Crosstalk between cancer cells and tumor-associated macrophages (TAMs) mediates tumor progression in colorectal cancer (CRC). Cytoplasmic polyadenylation element binding protein 3 (CPEB3) has been shown to exhibit tumor-suppressive role in CRC. Methods: The expression of CPEB3, CD68, CD86 and CD163 was determined in CRC tissues. SW480 or HCT116 cells overexpressing CPEB3 and LoVo or RKO cells with CPEB3 knockdown were constructed. Stably transfected CRC cells were co-cultured with THP-1 macrophages to determine the malignant phenotype of CRC cells, macrophage polarization, and secretory signals. The inhibition of CPEB3 on tumor progression and M2-like TAM polarization was confirmed in nude mice. Results: Decreased CPEB3 expression in CRC was associated with fewer CD86+ TAMs and more CD163+ TAMs. CPEB3 knockdown in CRC cells increased the number of CD163+ TAMs and the expression of IL1RA, IL-6, IL-4 and IL-10 in TAM supernatants. TAMs enhanced CRC cell proliferation and invasion via IL-6, and then activated the IL-6R/STAT3 pathway in CRC cells. However, CPEB3 reduced the IL-6R protein levels by directly binding to IL-6R mRNA, leading to decreased phosphorylated-STAT3 expression in CRC cells. CCL2 was significantly increased in CPEB3 knockdown cells, while CCL2 antibody treatment rescued the effect of CPEB3 knockdown in promoting CD163+ TAM polarization. Eventually, we confirmed that CPEB3 inhibits tumor progression and M2-like TAM polarization in vivo. Conclusions: CPEB3 is involved in the crosstalk between CRC cells and TAMs by targeting IL-6R/STAT3 signaling.

scholarly journals CPEB3 inhibits epithelial-mesenchymal transition by disrupting the crosstalk between colorectal cancer cells and tumor-associated macrophages via IL-6R/STAT3 signaling

2020 ◽  
Author(s):  
Qian Zhong ◽  
Yuxin Fang ◽  
Qiuhua Lai ◽  
Shanci Wang ◽  
Chengcheng He ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Macrophage Polarization ◽  
Tumor Associated Macrophages ◽  
Antibody Treatment ◽  
Mesenchymal Transition ◽  
Stat3 Signaling

Abstract Background: Crosstalk between cancer cells and tumor-associated macrophages (TAMs) mediates tumor progression in colorectal cancer (CRC). Cytoplasmic polyadenylation element binding protein 3 (CPEB3) has been shown to exhibit tumor-suppressive role in CRC.Methods: The expression of CPEB3, CD68, CD86 and CD163 was determined in CRC tissues. SW480 or HCT116 cells overexpressing CPEB3 and LoVo or RKO cells with CPEB3 knockdown were constructed. Stably transfected CRC cells were co-cultured with THP-1 macrophages to determine the malignant phenotype of CRC cells, macrophage polarization, and secretory signals. The inhibition of CPEB3 on tumor progression and M2-like TAM polarization was confirmed in nude mice.Results: Decreased CPEB3 expression in CRC was associated with fewer CD86+ TAMs and more CD163+ TAMs. CPEB3 knockdown in CRC cells increased the number of CD163+ TAMs and the expression of IL1RA, IL-6, IL-4 and IL-10 in TAM supernatants. TAMs enhanced CRC cell proliferation and invasion via IL-6, and then activated the IL-6R/STAT3 pathway in CRC cells. However, CPEB3 reduced the IL-6R protein levels by directly binding to IL-6R mRNA, leading to decreased phosphorylated-STAT3 expression in CRC cells. CCL2 was significantly increased in CPEB3 knockdown cells, while CCL2 antibody treatment rescued the effect of CPEB3 knockdown in promoting CD163+ TAM polarization. Eventually, we confirmed that CPEB3 inhibits tumor progression and M2-like TAM polarization in vivo. Conclusions: CPEB3 is involved in the crosstalk between CRC cells and TAMs by targeting IL-6R/STAT3 signaling.

scholarly journals CPEB3 inhibits epithelial-mesenchymal transition by disrupting the crosstalk between colorectal cancer cells and tumor-associated macrophages via IL-6R/STAT3 signaling

2020 ◽  
Author(s):  
Qian Zhong ◽  
Yuxin Fang ◽  
Qiuhua Lai ◽  
Shanci Wang ◽  
Chengcheng He ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Macrophage Polarization ◽  
Tumor Associated Macrophages ◽  
Antibody Treatment ◽  
Mesenchymal Transition ◽  
Stat3 Signaling

Abstract Background: Crosstalk between cancer cells and tumor-associated macrophages (TAMs) mediates tumor progression in colorectal cancer (CRC). Cytoplasmic polyadenylation element binding protein 3 (CPEB3) has been proved to exhibit tumor suppressive role in CRC.Methods: The expression of CPEB3, CD86 and CD163 was determined in CRC tissues. SW480 or HCT116 cells with overexpressed CPEB3 and LoVo or RKO cells with knockdown CPEB3 were constructed. Stably transfected CRC cells were co-cultured with THP-1 macrophages to determine the malignant phenotype of CRC cells, the macrophage polarization and the secretory signals. The inhibition of CPEB3 on tumor progression and M2-like TAM polarization was confirmed in nude mice.Results: Decreased CPEB3 expression in CRC was associated with less CD86+ TAMs number and more CD163+ TAMs number. CPEB3 knockdown in CRC cells increased CD163+ TAMs number and the expression of IL1RA, IL-6, IL-4 and IL-10 in TAMs supernatants. TAMs enhanced CRC cells proliferation and invasion via IL-6, then activated the IL-6R/STAT3 pathway in CRC cells. However, CPEB3 reduced the IL-6R protein level by directly binding to IL-6R mRNA, leading to decreased phosphorylated-STAT3 expression in CRC cells. CCL2 was significantly increased in knockdown CPEB3 cells, while CCL2 antibody treatment rescued the effect of knockdown CPEB3 on promoting CD163+ TAMs polarization. Eventually, we confirmed that CPEB3 inhibits tumor progression and M2-like TAMs polarization in vivo. Conclusions: CPEB3 is involved in the crosstalk between CRC cells and TAMs by targeting IL-6R/STAT3 signaling.

scholarly journals A novel inhibitor of ADAM17 sensitizes colorectal cancer cells to 5-Fluorouracil by reversing Notch and epithelial-mesenchymal transition in vitro and in vivo

2018 ◽  
Vol 51 (5) ◽  
pp. e12480 ◽  
Author(s):  
Dan-Dan Li ◽  
Chang-Hao Zhao ◽  
Huai-Wei Ding ◽  
Qiong Wu ◽  
Tian-Shu Ren ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Colorectal Cancer Cells

scholarly journals CSN8 is a key regulator in hypoxia-induced epithelial–mesenchymal transition and dormancy of colorectal cancer cells

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Songwen Ju ◽  
Feng Wang ◽  
Yirong Wang ◽  
Songguang Ju
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Treatment Conditions ◽  
Colorectal Cancer Cells

AbstractHypoxic stress plays a pivotal role in cancer progression; however, how hypoxia drives tumors to become more aggressive or metastatic and adaptive to adverse environmental stress is still poorly understood. In this study, we revealed that CSN8 might be a key regulatory switch controlling hypoxia-induced malignant tumor progression. We demonstrated that the expression of CSN8 increased significantly in colorectal cancerous tissues, which was correlated with lymph node metastasis and predicted poor patient survival. CSN8 overexpression induces the epithelial-mesenchymal transition (EMT) process in colorectal cancer cells, increasing migration and invasion. CSN8 overexpression arrested cell proliferation, upregulated key dormancy marker (NR2F1, DEC2, p27) and hypoxia response genes (HIF-1α, GLUT1), and dramatically enhanced survival under hypoxia, serum deprivation, or chemo-drug 5-fluorouracil treatment conditions. In particular, silenced CSN8 blocks the EMT and dormancy processes induced by the hypoxia of 1% O2 in vitro and undermines the adaptive capacity of colorectal cancer cells in vivo. The further study showed that CSN8 regulated EMT and dormancy partly by activating the HIF-1α signaling pathway, which increased HIF-1α mRNA expression by activating NF-κB and stabilized the HIF-1α protein via HIF-1α de-ubiquitination. Taken together, CSN8 endows primary colorectal cancer cells with highly aggressive/metastatic and adaptive capacities through regulating both EMT and dormancy induced by hypoxia. CSN8 could serve as a novel prognostic biomarker for colorectal cancer and would be an ideal target of disseminated dormant cell elimination and tumor metastasis, recurrence, and chemoresistance prevention.

scholarly journals LncRNA SNHG16 Facilitates Liver Metastases of Colorectal Cancer by Modulating Circulating Tumor Cells (CTCs) Epithelial-Mesenchymal Transition (EMT) via a Positive Feedback Loop with YAP1/TEAD1 Complex

2020 ◽  
Author(s):  
Zhenxian Xiang ◽  
Guoquan Huang ◽  
Haitao Wu ◽  
Qiuming He ◽  
Chaogang Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Distant Metastasis ◽  
Feedback Loop ◽  
Epithelial Mesenchymal Transition ◽  
Positive Feedback Loop ◽  
Mesenchymal Transition

Abstract Background: Circulating tumor cells are important precursor of colorectal cancer metastasis, which attributes to the main cause of cancer-related death. The ability to adopt epithelial-mesenchymal transition (EMT) process facilitates CTCs generation, thereby overcoming metastatic bottlenecks and realizing distant metastasis. However, the potential molecular mechanism of CRC EMT remains largely unknown.Methods: RT-qPCR, immunohistochemical staining, and western blot were used to detect the expression of mRNA and protein in CRC. Loss- and gain-of-function approaches were performed to investigate the effect of SNHG16 on CRC cell phenotypes. Function assays, including wounding healing, transwell assay, and clone formation were used to assess the effect of SNHG16 on tumor biological behavior. Then, RNA immunoprecipitation, Chromatin Immunoprecipitation, Co-Immunoprecipitation, GST-pull down, biotin-labeled miR-195-5p pull down, and dual-luciferase assay were performed to uncover the underlying mechanism for molecular interaction. Finally, CRC nude mice xenograft model experiment was performed to evaluate the influence of SNHG16 on tumor progression in vivo Results: Compared with normal tissue and cell line, SNHG16 was significantly upregulated in CRC. Clinical investigation revealed that SNHG16 high expression was correlated with advanced TNM stage, distant metastasis, and poor prognosis of cancer patients. According to Loss- and gain-of-function experiment, SNHG16 could promote CRC proliferation, migration, invasion, EMT, mesenchymal-type CTCs (MCTCs) generation, and liver metastasis through YAP1 in vitro and in vivo. Mechanistic research indicates that, SNHG16 could act as miRNA sponge to sequester miR-195-5p on Ago2, thereby protecting YAP1 from repression and facilitating CRC liver metastasis and tumor progression. Moreover, YAP1 could combine with TEA Domain Transcription Factor 1 (TEAD1) to form a YAP1/TEAD1 complex, which could in turn bind to the promoter of SNHG16 and regulate its transcription. In addition, both of YAP1 and TEAD1 are indispensable during this process. Finally, we demonstrated that YAP1 significantly promoted the tumor progression, and SNHG16 could rescue the effect of YAP1 on tumor progressionConclusion: Herein, we clarified a hitherto unexplored positive feedback loop between SNHG16 and YAP1/TEAD1. These findings provided new sights in CRC liver metastasis, and it may act as a potential candidate in the treatment of CRC.

scholarly journals LncRNA RPPH1 promotes colorectal cancer metastasis by interacting with TUBB3 and by promoting exosomes-mediated macrophage M2 polarization

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Zhen-xing Liang ◽  
Hua-shan Liu ◽  
Feng-wei Wang ◽  
Li Xiong ◽  
Chi Zhou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Progression ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Resection ◽  
Poor Prognostic Factor ◽  
Mesenchymal Transition ◽  
M2 Polarization

Abstract Metastasis is a well-known poor prognostic factor in cancer. However, the mechanisms how long non-coding RNAs (lncRNAs) regulate metastasis in colorectal cancer (CRC) remain largely unknown. Besides, tumor-associated macrophages (TAMs) play an important role in tumor progression, yet the contribution of lncRNA-mediated crosstalk between TAMs and CRC cells to tumor progression is not well understood. In this study, we report that lncRNA RPPH1 was significantly upregulated in CRC tissues, and the RPPH1 overexpression was associated with advanced TNM stages and poor prognosis. RPPH1 was found to promote CRC metastasis in vitro and in vivo. Mechanistically, RPPH1 induced epithelial–mesenchymal transition (EMT) of CRC cells via interacting with β-III tubulin (TUBB3) to prevent its ubiquitination. Furthermore, CRC cell-derived exosomes transported RPPH1 into macrophages which mediate macrophage M2 polarization, thereby in turn promoting metastasis and proliferation of CRC cells. In addition, exosomal RPPH1 levels in blood plasma turned out to be higher in treatment-naive CRC patients but lower after tumor resection. Compared to CEA and CA199, exosomal RPPH1 in CRC plasma displayed a better diagnostic value (AUC = 0.86). Collectively, RPPH1 serves as a potential therapeutic and diagnostic target in CRC.

scholarly journals Tumor-associated macrophages: potential therapeutic strategies and future prospects in cancer

2021 ◽  
Vol 9 (1) ◽  
pp. e001341
Author(s):  
Chunxiao Li ◽  
Xiaofei Xu ◽  
Shuhua Wei ◽  
Ping Jiang ◽  
Lixiang Xue ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Poor Prognosis ◽  
Tumor Immunotherapy ◽  
Therapeutic Strategies ◽  
Preclinical Studies ◽  
Future Prospects ◽  
Tumor Associated Macrophages

Macrophages are the most important phagocytes in vivo. However, the tumor microenvironment can affect the function and polarization of macrophages and form tumor-associated macrophages (TAMs). Usually, the abundance of TAMs in tumors is closely associated with poor prognosis. Preclinical studies have identified important pathways regulating the infiltration and polarization of TAMs during tumor progression. Furthermore, potential therapeutic strategies targeting TAMs in tumors have been studied, including inhibition of macrophage recruitment to tumors, functional repolarization of TAMs toward an antitumor phenotype, and other therapeutic strategies that elicit macrophage-mediated extracellular phagocytosis and intracellular destruction of cancer cells. Therefore, with the increasing impact of tumor immunotherapy, new antitumor strategies to target TAMs are now being discussed.

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