Death receptor 6 promotes ovarian cancer cell migration through KIF11

Abstract

The expression of death receptor 6 ( DR 6) is abnormal in some cancer types, but the function and underlying molecular mechanisms of DR 6 in tumor progression are not yet clear. In the present study, our analysis of ovarian cancer RNA sequencing data from The Cancer Genome Atlas revealed that DR 6 is upregulated in human ovarian cancer. We confirmed that the expression level of DR 6 is upregulated in ovarian cancer tissues when compared with matched adjacent normal tissues. In addition, DR 6 enhanced ovarian carcinoma cell migration ability, and decreased expression of DR 6 inhibited the expression of matrix metalloprotease ( MMP ) 2 and MMP 9, and increased the expression of E‐cadherin. Additionally, DR 6 sh RNA caused a significant decrease in phosphoinositide‐3‐kinase ( PI 3K), phospho (p) ‐ AKT , p‐extracellular signal‐regulated kinase ( ERK ), and p‐mitogen‐activated protein kinase kinase expression in SKOV 3 cells. These results suggested that DR 6 can enhance ovarian carcinoma cell migration ability through the mitogen‐activated protein kinase/ ERK and PI 3K/ AKT pathways. Notably, mass spectrometric analysis indicated that DR 6 co‐purified with kinesin family member 11 ( KIF 11), and we verified the interaction between KIF 11 and DR 6 by co‐immunoprecipitation and glutathione S ‐transferase pull‐down. Furthermore, we demonstrated that DR 6 can bind tumor necrosis factor receptor‐associated factor 4 ( TRAF 4) with co‐immunoprecipitation. Overexpression of KIF 11 or TRAF 4 eliminated the suppression of carcinoma cell migration by DR 6 knockdown. We also found that TRAF 4 and KIF 11 were upregulated in ovarian carcinomas and that their level of expression was positively correlated with that of DR 6. The findings above suggest that DR 6 may play a notable oncogenic role in ovarian malignancy by interacting with TRAF 4 and KIF 11, and that DR 6 may be an effective therapeutic target in ovarian cancer.

Comparative Analysis on Abnormal Methylome of Differentially Expressed Genes and Disease Pathways in the Immune Cells of RA and SLE

“…Most importantly, over expression of IFIT1 or IFIT3 increased EGFR and AKT expression, which is closely related to the activation of the PI3K pathway (75). TOP2A can also activate the PI3K/AKT signaling pathway leading to cell migration (76), whereas an increased expression of KIF11 inhibited the activation of PI3K/AKT signaling pathway (77). In summary, the potential biomarker genes proposed for SLE diagnosis are closely related to PI3K pathway, and the use of PI3K inhibitors reversed the changes associated with ISG15, OAS1, OASL, and IFIT1 (72,78,79).…”

KIF11 Serves as an Independent Prognostic Factor and Therapeutic Target for Patients With Lung Adenocarcinoma

“…On the other hand, KIF11 is also associated with cell mobility. Relative to mass spectrometric analysis, Shi et al have found that KIF11 was co-purified with death receptor 6 (DR6), which could promote cellular migration capacity mediated by MAPK/ERK and PI3K/AKT signaling pathways for ovarian carcinoma (33). Meanwhile, KIF11 could reduce the inhibitory effects of DR6 knockdown on ovarian carcinoma cell migration, implying KIF11, to some extent, contributed to the cell mobility.…”

Integrated bioinformatics analysis for the screening of hub genes and therapeutic drugs in ovarian cancer

“…KIF11, a member of the kinesin-like protein family, was once identified as a hub gene in OC by Zhanzhan Xu et al [8], and they also found that KIF11 was potentially targeted by hsa-miR-424 and hsa-miR-381. A recent study explored whether death receptor 6 can promote OC cell migration by interacting with KIF11 and TNF receptor-associated factor 4 [40]. In this study, KIF11 was also considered a chemotherapy target for OC using cBioPortal (Fig.…”