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.

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Purpose: The evidence on the effect of gut microbiota on the accumulation of cardiovascular diseases (CVD) risk factors among children is scarce. We aimed to examine the alterations of gut microbiota with different numbers of CVD risk factors among children. Methods: Data were from the baseline study of the Huantai Childhood Cardiovascular Health Cohort Study in Zibo, China. We compared the differences in gut microbiota based on 16S rRNA gene sequencing among 72 children with different numbers of CVD risk factors matched by age and sex (i.e., none, one, two-or-more, 24 children for each group). Results: The community richness and diversity of gut microbiota decreased with an increased number of CVD risk factors in children (P for trend<0.05). The β-diversity analyses indicated a significant separation in the community composition among the three groups. Among genera with relative abundance greater than 0.01%, the relative abundance of Lachnoclostridium (PFDR=0.009) increased in the CVD risk groups, whereas Alistipes (PFDR<0.001) and Lachnospiraceae_NK4A136_group (PFDR=0.043) decreased in the CVD risk groups compared to the non-risk group. The receiver operating characteristic (ROC) analyses showed that genus Christensenellaceae_R-7_group performed a high ability in identifying one and two-or-more risk from non-risk (area under the ROC curve [AUC]: 0.84-0.92), and genera Family_XIII_AD3011_group (AUC: 0.73-0.91) and Lachnoclostridium (AUC:0.77-0.80) performed moderate abilities in identifying none, one, and two-or-more CVD risk factors in children. The disorders of gut microbiota participating in the D-Glutamine and D-glutamate metabolism and cysteine and methionine metabolism pathways might lead to the accumulation of CVD risk factors in children. Conclusions: Dysbiosis of gut microbiota particularly for genera Christensenellaceae_R-7_group, Family_XIII_AD3011_group, and Lachnoclostridium may contribute to the early detection and the accumulation of CVD risk factors in childhood.