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Decreased NSG3 enhances PD-L1 expression by Erk1/2 pathway to promote pancreatic cancer progress.

ABSTRACT: Inhibiting the functioning of PD-1/PD-L1 to activate human immune system and improve the prognosis of pancreatic cancer (PC) would provide a significant boost to handling the disease. One research found the expression level of NSG3 was reduced in pediatric pilocytic astrocytoma, so is PC and we found NSG3 could regulate the expression of PD-L1. So NSG3 could become a new target for enhancing the immune response to PC. The GEPIA website was employed to analyze the prognoses in PC patients with different NSG3 levels. Immunohistochemistry (IHC) analysis was applied to detect different levels of NSG3 in para-PC and PC tissues. Cell biological function tests (in vitro) were performed and a subcutaneous nude mice tumor model (in vivo) was established to verify the effect of NSG3 on PC. Immunoblotting and RT-qPCR were utilized to demonstrate the inhibiting effect of NSG3 on PD-L1 through regulating Erk1/2 phosphorylation. A subcutaneous C57BL/6 tumor mice model was established to assess the possibility of a synergistic effect of NSG3 expression and the use of an anti-PD-L1 antibody on PC. PC tissues had decreased NSG3 expression levels, which led to poor prognosis. Overexpressing NSG3 suppressed proliferation, invasion and migration capacities of PC cells. On the contrary, knocking-down NSG3 prompted PC malignancy whether in vivo or in vitro. Importantly, NSG3 prevented Erk1/2 phosphorylation to inhibit PD-L1 expression. Additionally, NSG3 and an immune checkpoint inhibitor anti-PD-1 antibody acted synergistically, which enhanced the efficacy of the inhibitor. NSG3 inhibited PD-L1 expression by suppressing Erk1/2 phosphorylation to improve the immune response to PC. NSG3 is, therefore, a potential new diagnostic and prognostic marker, particularly useful in immune checkpoint blockade therapy.

SUBMITTER: Xia X

PROVIDER: S-EPMC7994162 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundFibulin-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.MethodThe 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.ResultEFEMP2 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.ConclusionEFEMP2 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.

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Decreased NSG3 enhances PD-L1 expression by Erk1/2 pathway to promote pancreatic cancer progress.

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