Cyclooxygenase-2 in tumor-associated macrophages promotes metastatic potential of breast cancer cells through Akt pathway

Gan, Lu; Qiu, Zhu; Huang, Jing; Li, Yunhai; Huang, Hongyan; Xiang, Tingxiu; Wan, Jingyuan; Hui, Tianli; Lin, Yong; Li, Hongzhong; Ren, Guosheng

doi:10.7150/ijbs.15943

Cited by 61 publications

(51 citation statements)

References 56 publications

(62 reference statements)

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“…For example, COX‐2 inhibitors also suppress tumor immune evasion by inhibiting M2 macrophages and T regulatory cells 41,42 . Cyclooxygenase‐2 in tumor‐associated macrophages (TAMs) promotes breast cancer metastasis through the induction of MMP9 and the promotion of EMT in tumor cells 43 . In addition, cancer‐associated fibroblasts (CAFs) are major sources of COX‐2/PGE 2 in the tumor microenvironment 44 .…”

Section: Discussionmentioning

confidence: 99%

Epidermal growth factor‐induced COX‐2 regulates metastasis of head and neck squamous cell carcinoma through upregulation of angiopoietin‐like 4

et al. 2020

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Epidermal growth factor receptor (EGFR) expression and activation are the major causes of metastasis in cancers such as head and neck squamous cell carcinoma (HNSCC). However, the reciprocal effect of EGF‐induced COX‐2 and angiopoietin‐like 4 (ANGPTL4) on HNSCC metastasis remains unclear. In this study, we revealed that the expression of ANGPTL4 is essential for COX‐2‐derived prostaglandin E2 (PGE2)‐induced tumor cell metastasis. We showed that EGF‐induced ANGPTL4 expression was dramatically inhibited with the depletion and inactivation of COX‐2 by knockdown of COX‐2 and celecoxib treatment, respectively. Prostaglandin E2 induced ANGPTL4 expression in a time‐ and dose‐dependent manners in various HNSCC cell lines through the ERK pathway. In addition, the depletion of ANGPTL4 and MMP1 significantly impeded the PGE2‐induced transendothelial invasion ability of HNSCC cells and the binding of tumor cells to endothelial cells. The induction of molecules involved in the regulation of epithelial‐mesenchymal transition was also dependent on ANGPTL4 expression in PGE2‐treated cells. The depletion of ANGPTL4 further blocked PGE2‐primed tumor cell metastatic seeding of lungs. These results indicate that the EGF‐activated PGE2/ANGPTL4 axis enhanced HNSCC metastasis. The concurrent expression of COX‐2 and ANGPTL4 in HNSCC tumor specimens provides insight into potential therapeutic targets for the treatment of EGFR‐associated HNSCC metastasis.

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Section: Discussionmentioning

confidence: 99%

Epidermal growth factor‐induced COX‐2 regulates metastasis of head and neck squamous cell carcinoma through upregulation of angiopoietin‐like 4

et al. 2020

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“…As it has been discussed, NF‐κβ is a transactivator for COX‐2 promoter contributed to activation of COX‐2 in both cancer cells (Charalambous et al, ) and TAMs (Hung et al, ). There is also evidence for protumoral activity of COX‐2 in macrophages (Lu Gan et al, ). Taken together, it could be speculated that macrophage polarity is not influenced by COX‐2.…”

Section: Contribution Of Cox‐2‐expressing Tumor‐associated Macrophagementioning

confidence: 99%

Cyclooxygenase‐2 in cancer: A review

Goradel

Najafi

Salehi

et al. 2018

Journal Cellular Physiology

572

399

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Cyclooxygenase-2 (COX-2) is frequently expressed in many types of cancers exerting a pleiotropic and multifaceted role in genesis or promotion of carcinogenesis and cancer cell resistance to chemo-and radiotherapy. COX-2 is released by cancerassociated fibroblasts (CAFs), macrophage type 2 (M2) cells, and cancer cells to the tumor microenvironment (TME). COX-2 induces cancer stem cell (CSC)-like activity, and promotes apoptotic resistance, proliferation, angiogenesis, inflammation, invasion, and metastasis of cancer cells. COX-2 mediated hypoxia within the TME along with its positive interactions with YAP1 and antiapoptotic mediators are all in favor of cancer cell resistance to chemotherapeutic drugs. COX-2 exerts most of the functions through its metabolite prostaglandin E2. In some and limited situations, COX-2 may act as an antitumor enzyme. Multiple signals are contributed to the functions of COX-2 on cancer cells or its regulation. Members of mitogen-activated protein kinase (MAPK) family, epidermal growth factor receptor (EGFR), and nuclear factor-κβ are main upstream modulators for COX-2 in cancer cells. COX-2 also has interactions with a number of hormones within the body. Inhibition of COX-2 provides a high possibility to exert therapeutic outcomes in cancer. Administration of COX-2 inhibitors in a preoperative setting could reduce the risk of metastasis in cancer patients. COX-2 inhibition also sensitizes cancer cells to treatments like radioand chemotherapy. Chemotherapeutic agents adversely induce COX-2 activity. Therefore, choosing an appropriate chemotherapy drugs along with adjustment of the type and does for COX-2 inhibitors based on the type of cancer would be an effective adjuvant strategy for targeting cancer.

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“…Recently, it has been reported that cyclooxygenase 2 (COX-2) and prostaglandin E2 (PGE2) regulate cancer progression and metastasis [ 5 , 6 ]. Overexpression of COX-2 in tumor-associated macrophages promotes pro-metastatic effects of breast cancer cells by regulating MMP-9 and EMT and Akt pathway, and the COX-2/PGE2 axis mediates cell invasion in EGF-induced ovarian cancer [ 7 , 8 ]. Especially, PGE2 produced by inducible COX-2 and mPGES-1 promotes cancer cell proliferation in vitro and in vivo , and induced EMT in prostate cancer [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

MiRNA-206 suppresses PGE2-induced colorectal cancer cell proliferation, migration, and invasion by targetting TM4SF1

et al. 2018

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MiRNA (miR)-206 plays a tumor suppressor role in various cancer types. Here, we investigated whether miR-206 is involved in prostaglandin E2 (PGE2)-induced epithelial–mesenchymal transition (EMT) in colorectal cancer (CRC) cells through the targetting of transmembrane 4 L six family member 1 (TM4SF1).The effect of PGE2 on growth and apoptosis of CRC cells was evaluated using the MTT assay and flow cytometry analysis, respectively. TM4SF1 and miR-206 expression levels were determined with quantitative polymerase chain reaction (qRT-PCR) in CRC tissues and cell lines. The concentration of PGE2 in the serum of CRC patients and healthy controls was measured with an ELISA kit. A miR-206 or TM4SF1 construct was transfected into cells with PGE2. Transwell migration and invasion assays were used to examine cell migration and invasion properties. Additionally, a luciferase assay was performed to determine whether TM4SF1 was directly targetted by miR-206.We found that miR-206 was down-regulated and TM4SF1 was up-regulated in human CRC tissues and cell lines. Moreover, miR-206 was negatively correlated with TM4SF1 expression. Bioinformatics analysis and a luciferase reporter assay revealed that miR-206 directly targetted the 3′-untranslated region (UTR) of TM4SF1, and TM4SF1 expression was reduced by miR-206 overexpression at both the mRNA and protein levels. Additionally, PGE2 significantly suppressed the expression of miR-206 and increased the expression of TM4SF1 in CRC cells. PGE2 induction led to enhanced CRC cell proliferation, migration, and invasion. Moreover, the overexpression of miR-206 decreased CRC cell proliferation, migration, and invasion compared with control group in PGE2-induced cells, and these effects could be recovered by the overexpression of TM4SF1. Overexpression of miR-206 also suppressed the expression of β-catenin, VEGF, MMP-9, Snail, and Vimentin and enhanced E-cadherin expression in PGE2-induced cells. These results could be reversed by the overexpression of TM4SF1. At last, up-regulation of miR-206 suppressed expression of p-AKT and p-ERK by targetting TM4SF1 in PGE2-induced cells.Our results provide further evidence that miR-206 has a protective effect on PGE2-induced colon carcinogenesis.

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Cyclooxygenase-2 in tumor-associated macrophages promotes metastatic potential of breast cancer cells through Akt pathway

Cited by 61 publications

References 56 publications

Epidermal growth factor‐induced COX‐2 regulates metastasis of head and neck squamous cell carcinoma through upregulation of angiopoietin‐like 4

Epidermal growth factor‐induced COX‐2 regulates metastasis of head and neck squamous cell carcinoma through upregulation of angiopoietin‐like 4

Cyclooxygenase‐2 in cancer: A review

MiRNA-206 suppresses PGE2-induced colorectal cancer cell proliferation, migration, and invasion by targetting TM4SF1

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