Cyclooxygenase-2 induced β1-integrin expression in NSCLC and promoted cell invasion via the EP1/MAPK/E2F-1/FoxC2 signal pathway

Pan, Jinshun; Yang, Qinyi; Shao, Jiaofang; Zhang, Li; Ma, Juan; Wang, Yipin; Jiang, Bing-Hua; Leng, Jing; Bai, Xu

doi:10.1038/srep33823

Cited by 36 publications

(34 citation statements)

References 34 publications

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“…These results reveal that the PGE 2 /ANGPTL4 axis regulates tumor cell migration and invasion through the promotion of tumor‐endothelial cell interactions. In addition, previous reports indicated that COX‐2 enhances β1 integrin expression to promote non‐small‐cell lung cancer cell invasion 48 . In our previous studies, we have shown that EGF‐induced ANGPTL4 activates the integrin pathway to promote HNSCC metastasis 5 .…”

Section: Discussionmentioning

confidence: 82%

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: 82%

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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“…This seminal study and others to follow identified FOXC2 as a key regulator of EMT, a pathway key to tumor cell metastasis that is driven by FOXC2's direct repression of p120ctn and direct induction of Zeb1 (23,24), both of which lead to down-regulation of E-cadherin, a major hallmark of EMT. In another study, FOXC2 has been shown to promote non-small cell lung cancer cell migration and invasion through up-regulation of Itgb1 gene expression (25). It has also been shown to drive osteosarcoma metastasis to lung tissue via a CXCR4-dependent mechanism (26).…”

Section: Discussionmentioning

confidence: 96%

The FOXC2 Transcription Factor Promotes Melanoma Outgrowth and Regulates Expression of Genes Associated With Drug Resistance and Interferon Responsiveness

Hargadon

Győrffy

Strong

et al. 2019

Cancer Genomics Proteomics

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Background/Aim: The FOXC2 transcription factor promotes the progression of several cancer types, but has not been investigated in the context of melanoma cells. To study FOXC2's influence on melanoma progression, we generated a FOXC2-deficient murine melanoma cell line and evaluated The Cancer Genome Atlas (TCGA) patient datasets. Materials and Methods: We compared tumor growth kinetics and RNA-seq/qRT-PCR gene expression profiles from wild-type versus FOXC2-deficient murine melanomas. We also performed Kaplan-Meier survival analysis of TCGA data to assess the influence of FOXC2 gene expression on melanoma patients' response to chemotherapy and immunotherapy. Results: FOXC2 promotes melanoma progression and regulates the expression of genes associated with multiple oncogenic pathways, including the oxidative stress response, xenobiotic metabolism, and interferon responsiveness. FOXC2 expression in melanoma correlates negatively with patient response to chemotherapy and immunotherapy. Conclusion: FOXC2 drives a tumor-promoting gene expression program in melanoma and is a prognostic indicator of patient response to multiple cancer therapies. Melanoma, a highly aggressive form of cancer arising from pigment-producing melanocytes, is responsible for the majority of skin cancer-related mortality, accounting for~6 0,000 annual deaths worldwide (1). Importantly, the incidence of melanoma has risen substantially over the last 40 years (2), a trend that is expected to continue to at least 2031 (3). Although surgical removal of primary lesions is typically successful in the treatment of early-stage disease, many melanoma patients are not diagnosed until later stages of metastatic disease in which surgery is either not possible or largely ineffective. Unfortunately, malignant melanoma is highly resistant to radiation and chemotherapy, and the only FDA-approved chemotherapeutic for the treatment of melanoma, dacarbazine (DTIC), has a minimal impact on patient survival (4). While advances in targeted therapy and immunotherapy have improved the prognosis for melanoma in recent years, there are still patients who do not respond to these regimens, and relapse of therapy-resistant tumors remains an ongoing challenge in many patients who do achieve clinical benefit (5, 6). Therefore, in order to improve the clinical outcome of melanoma patients going forward, it is necessary to gain additional insight into factors that promote melanoma progression and resistance to these therapeutic modalities. FOXC2 is a member of the forkhead box family of transcription factors that control a variety of cellular processes in embryonic and adult tissues. In addition to its normal regulation of development, growth, and metabolism in various tissue types, FOXC2 has recently emerged as a driver of several hallmarks of cancer progression as well. Within vascular endothelial cells, FOXC2 promotes expression of multiple genes that enhance angiogenesis (7-9). FOXC2 can also become overexpressed or dysregulated in tumor cells themselves, where it is asso...

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“…It has been reported that COX2 is upregulated in different cancers and its elevation results in a poor prognosis such as axillary node and bone metastases, and chemotherapy resistance [ 22 – 26 ]. Inhibition of COX2 can act in a concerted way with improved therapeutic potential in invasive breast cancer, non small cell lung cancer, bladder cancer and cervical cancer [ 18 , 27 – 29 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of COX2 enhances the chemosensitivity of dichloroacetate in cervical cancer cells

Xiong

et al. 2017

Oncotarget

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Dichloroacetate (DCA), a traditional mitochondria-targeting agent, has shown promising prospect as a sensitizer in fighting against malignancies including cervical cancer. But it is unclear about the effect of DCA alone on cervical tumor. Moreover, previous reports have demonstrated that the increased cyclooxygenase-2 (COX2) expression is associated with chemoresistance and poor prognosis of cervical cancer. However, it is still unknown whether COX2 can affect the sensitivity of DCA in cervical cancer cells. In this study, we found that cervical cancer cells were insensitive to DCA. Furthermore, we for the first time revealed that DCA could upregulate COX2 which impeded the chemosensitivity of DCA in cervical cancer cells. Mechanistic study showed that DCA reduced the level of RNA binding protein quaking (QKI), leading to the decay suppression of COX2 mRNA and the subsequent elevation of COX2 protein. Inhibition of COX2 using celecoxib could sensitize DCA in repressing the growth of cervical cancer cells both in vitro and in vivo. These results indicate that COX2 is a novel resistance factor of DCA, and combination of celecoxib with DCA may be beneficial to the treatment of cervical cancer.

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Cyclooxygenase-2 induced β1-integrin expression in NSCLC and promoted cell invasion via the EP1/MAPK/E2F-1/FoxC2 signal pathway

Cited by 36 publications

References 34 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

The FOXC2 Transcription Factor Promotes Melanoma Outgrowth and Regulates Expression of Genes Associated With Drug Resistance and Interferon Responsiveness

Inhibition of COX2 enhances the chemosensitivity of dichloroacetate in cervical cancer cells

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