Dataset Information

TR4 nuclear receptor suppresses HCC cell invasion via downregulating the EphA2 expression.

ABSTRACT: Early studies indicated that testicular nuclear receptor 4 (TR4) could function as a suppressor in the transcriptional regulation of the HBV core gene expression, which might then influence the development of hepatocellular carcinoma (HCC). The direct linkage between TR4 and HCC progression, however, remained unclear. Here, via a human clinical sample survey, we found that 13 of the 18 HCC patients studied had lower TR4 expression in metastatic lesions than in matched primary HCC lesions, suggesting that TR4 may play a negative role in HCC metastasis. Results from in vitro cell migration/invasion studied confirmed that TR4 could suppress HCC cell migration/invasion. Mechanism dissection revealed that TR4 might function through downregulating ephrin type-A receptor 2 (EphA2) expression at the transcriptional level via direct binding to the TR4REs located on the 5' promoter of EphA2 to suppress HCC cell migration/invasion. Targeting the EphA2 via EphA2-siRNA partially reversed the enhanced HCC cell migration/invasion with confirmed TR4 knockdown. Notably, results from preclinical studies using in vivo mouse model with orthotopic xenograft of HCC LM3 cells also confirmed the in vitro findings. Taking these findings together, preclinical studies using multiple in vitro HCC cell lines and an in vivo mouse model all led to the conclusion that TR4 may function as a suppressor of HCC metastasis and that targeting this newly identified TR4-EphA2 signaling may improve our ability to suppress HCC metastasis.

SUBMITTER: Jin R

PROVIDER: S-EPMC5833398 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

TR4 nuclear receptor suppresses HCC cell invasion via downregulating the EphA2 expression.

Jin Ren'an R Lin Hui H Li Gonghui G Xu Junjie J Shi Liang L Chang Chawnshang C Cai Xiujun X

Cell death & disease 20180215 3

Early studies indicated that testicular nuclear receptor 4 (TR4) could function as a suppressor in the transcriptional regulation of the HBV core gene expression, which might then influence the development of hepatocellular carcinoma (HCC). The direct linkage between TR4 and HCC progression, however, remained unclear. Here, via a human clinical sample survey, we found that 13 of the 18 HCC patients studied had lower TR4 expression in metastatic lesions than in ma ...[more]

PMID: 29449527

Similar Datasets

Project description:The obligate intracellular bacterium Chlamydia trachomatis invades into host cells to replicate inside a membrane-bound vacuole called inclusion. Multiple different host proteins are recruited to the inclusion and are functionally modulated to support chlamydial development. Invaded and replicating Chlamydia induces a long-lasting activation of the PI3 kinase signaling pathway that is required for efficient replication. We identified the cell surface tyrosine kinase EphrinA2 receptor (EphA2) as a chlamydial adherence and invasion receptor that induces PI3 kinase (PI3K) activation, promoting chlamydial replication. Interfering with binding of C. trachomatis serovar L2 (Ctr) to EphA2, downregulation of EphA2 expression or inhibition of EphA2 activity significantly reduced Ctr infection. Ctr interacts with and activates EphA2 on the cell surface resulting in Ctr and receptor internalization. During chlamydial replication, EphA2 remains active accumulating around the inclusion and interacts with the p85 regulatory subunit of PI3K to support the activation of the PI3K/Akt signaling pathway that is required for normal chlamydial development. Overexpression of full length EphA2, but not the mutant form lacking the intracellular cytoplasmic domain, enhanced PI3K activation and Ctr infection. Despite the depletion of EphA2 from the cell surface, Ctr infection induces upregulation of EphA2 through the activation of the ERK pathway, which keeps the infected cell in an apoptosis-resistant state. The significance of EphA2 as an entry and intracellular signaling receptor was also observed with the urogenital C. trachomatis-serovar D. Our findings provide the first evidence for a host cell surface receptor that is exploited for invasion as well as for receptor-mediated intracellular signaling to facilitate chlamydial replication. In addition, the engagement of a cell surface receptor at the inclusion membrane is a new mechanism by which Chlamydia subverts the host cell and induces apoptosis resistance.

Dataset Information

TR4 nuclear receptor suppresses HCC cell invasion via downregulating the EphA2 expression.

Publications

TR<sub>4</sub> nuclear receptor suppresses HCC cell invasion via downregulating the EphA2 expression.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets