EFEMP2 upregulates PD-L1 expression via EGFR/ERK1/2/c-Jun signaling to promote the invasion of ovarian cancer cells
Abstract Background Fibulin-like extracellular matrix protein 2 (EFEMP2) has been reported to be related to the progression of various cancers. We have previously reported that EFEMP2 was highly expressed in ovarian cancer and was strongly associated with poor prognosis in patients. This study inten...
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| Format: | Article |
| Language: | English |
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BMC
2023-07-01
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| Series: | Cellular & Molecular Biology Letters |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s11658-023-00471-8 |
| _version_ | 1797784489309503488 |
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| author | Xin Shen Xuli Jin Shuang Fang Jie Chen |
| author_facet | Xin Shen Xuli Jin Shuang Fang Jie Chen |
| author_sort | Xin Shen |
| collection | DOAJ |
| description | Abstract Background Fibulin-like extracellular matrix protein 2 (EFEMP2) has been reported to be related to the progression of various cancers. We have previously reported that EFEMP2 was highly expressed in ovarian cancer and was strongly associated with poor prognosis in patients. This study intends to further explore its interacting proteins and possible downstream signaling pathways. Method The expression of EFEMP2 was detected by RT-qPCR, ICC and western blot in 4 kinds of ovarian cancer cells with different migration and invasion ability. Cell models with strong or weak EFEMP2 expression were constructed by lentivirus transfection. The effects of the down-regulation and up-regulation of EFEMP2 on the biological behavior of ovarian cancer cells were studied through in-vitro and in-vivo functional tests. The phosphorylation pathway profiling array and KEGG database analyses identified the downstream EGFR/ERK1/2/c-Jun signaling pathway and the programmed death-1 (PD-L1) pathway enrichment. Additionally, the protein interaction between EFEMP2 and EGFR was detected by immunoprecipitation. Result EFEMP2 was positively correlated with the invasion ability of ovarian cancer cells, its down-regulation inhibited the migrative, invasive and cloning capacity of cancer cells in vitro and suppressed the tumor proliferation and intraperitoneal diffusion in vivo, while its up-regulation did the opposite. Moreover, EFEMP2 could bind to EGFR to induce PD-L1 regulation in ovarian cancer, which was caused by the activation of EGFR/ERK1/2/c-Jun signaling. Similar to EFEMP2, PD-L1 was also highly expressed in aggressive cells and had the ability to promote the invasion and metastasis of ovarian cancer cells both in vitro and in vivo, and PD-L1 upregulation was partly caused by EFEMP2 activation. Afatinib combined with trametinib had an obvious effect of inhibiting the intraperitoneal diffusion of ovarian cancer cells, especially in the group with low expression of EFEMP2, while overexpression of PD-L1 could reverse this phenomenon. Conclusion EFEMP2 could bind to EGFR to activate ERK1/2/c-Jun pathway and regulate PD-L1 expression, furthermore PD-L1 was extremely essential for EFEMP2 to promote ovarian cancer cells invasion and dissemination in vitro and in vivo. Targeted therapy against the source gene EFEMP2 is our future research direction, which may better inhibit the invasion and metastasis of ovarian cancer cells. |
| first_indexed | 2024-03-13T00:40:38Z |
| format | Article |
| id | doaj.art-689dc3296ded4983b97eb562263d560c |
| institution | Directory Open Access Journal |
| issn | 1689-1392 |
| language | English |
| last_indexed | 2024-03-13T00:40:38Z |
| publishDate | 2023-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Cellular & Molecular Biology Letters |
| spelling | doaj.art-689dc3296ded4983b97eb562263d560c2023-07-09T11:19:25ZengBMCCellular & Molecular Biology Letters1689-13922023-07-0128112510.1186/s11658-023-00471-8EFEMP2 upregulates PD-L1 expression via EGFR/ERK1/2/c-Jun signaling to promote the invasion of ovarian cancer cellsXin Shen0Xuli Jin1Shuang Fang2Jie Chen3Department of Maternal and Child Health, School of Public Health, Cheeloo College of Medicine, Shandong UniversityDepartment of Epidemiology, School of Public Health, Cheeloo College of Medicine, Shandong UniversityJinan Medical Center Management CommitteeDepartment of Maternal and Child Health, School of Public Health, Cheeloo College of Medicine, Shandong UniversityAbstract Background Fibulin-like extracellular matrix protein 2 (EFEMP2) has been reported to be related to the progression of various cancers. We have previously reported that EFEMP2 was highly expressed in ovarian cancer and was strongly associated with poor prognosis in patients. This study intends to further explore its interacting proteins and possible downstream signaling pathways. Method The expression of EFEMP2 was detected by RT-qPCR, ICC and western blot in 4 kinds of ovarian cancer cells with different migration and invasion ability. Cell models with strong or weak EFEMP2 expression were constructed by lentivirus transfection. The effects of the down-regulation and up-regulation of EFEMP2 on the biological behavior of ovarian cancer cells were studied through in-vitro and in-vivo functional tests. The phosphorylation pathway profiling array and KEGG database analyses identified the downstream EGFR/ERK1/2/c-Jun signaling pathway and the programmed death-1 (PD-L1) pathway enrichment. Additionally, the protein interaction between EFEMP2 and EGFR was detected by immunoprecipitation. Result EFEMP2 was positively correlated with the invasion ability of ovarian cancer cells, its down-regulation inhibited the migrative, invasive and cloning capacity of cancer cells in vitro and suppressed the tumor proliferation and intraperitoneal diffusion in vivo, while its up-regulation did the opposite. Moreover, EFEMP2 could bind to EGFR to induce PD-L1 regulation in ovarian cancer, which was caused by the activation of EGFR/ERK1/2/c-Jun signaling. Similar to EFEMP2, PD-L1 was also highly expressed in aggressive cells and had the ability to promote the invasion and metastasis of ovarian cancer cells both in vitro and in vivo, and PD-L1 upregulation was partly caused by EFEMP2 activation. Afatinib combined with trametinib had an obvious effect of inhibiting the intraperitoneal diffusion of ovarian cancer cells, especially in the group with low expression of EFEMP2, while overexpression of PD-L1 could reverse this phenomenon. Conclusion EFEMP2 could bind to EGFR to activate ERK1/2/c-Jun pathway and regulate PD-L1 expression, furthermore PD-L1 was extremely essential for EFEMP2 to promote ovarian cancer cells invasion and dissemination in vitro and in vivo. Targeted therapy against the source gene EFEMP2 is our future research direction, which may better inhibit the invasion and metastasis of ovarian cancer cells.https://doi.org/10.1186/s11658-023-00471-8Ovarian cancerEFEMP2PD-L1EGFRERK1/2/c-Jun pathwayTrametinib |
| spellingShingle | Xin Shen Xuli Jin Shuang Fang Jie Chen EFEMP2 upregulates PD-L1 expression via EGFR/ERK1/2/c-Jun signaling to promote the invasion of ovarian cancer cells Cellular & Molecular Biology Letters Ovarian cancer EFEMP2 PD-L1 EGFR ERK1/2/c-Jun pathway Trametinib |
| title | EFEMP2 upregulates PD-L1 expression via EGFR/ERK1/2/c-Jun signaling to promote the invasion of ovarian cancer cells |
| title_full | EFEMP2 upregulates PD-L1 expression via EGFR/ERK1/2/c-Jun signaling to promote the invasion of ovarian cancer cells |
| title_fullStr | EFEMP2 upregulates PD-L1 expression via EGFR/ERK1/2/c-Jun signaling to promote the invasion of ovarian cancer cells |
| title_full_unstemmed | EFEMP2 upregulates PD-L1 expression via EGFR/ERK1/2/c-Jun signaling to promote the invasion of ovarian cancer cells |
| title_short | EFEMP2 upregulates PD-L1 expression via EGFR/ERK1/2/c-Jun signaling to promote the invasion of ovarian cancer cells |
| title_sort | efemp2 upregulates pd l1 expression via egfr erk1 2 c jun signaling to promote the invasion of ovarian cancer cells |
| topic | Ovarian cancer EFEMP2 PD-L1 EGFR ERK1/2/c-Jun pathway Trametinib |
| url | https://doi.org/10.1186/s11658-023-00471-8 |
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