Death receptor 6 promotes ovarian cancer cell migration through KIF11.

The expression of death receptor 6 (DR6) is abnormal in some cancer types, but the function and underlying molecular mechanisms of DR6 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 DR6 is upregulated in human ovarian cancer. We confirmed that the expression level of DR6 is upregulated in ovarian cancer tissues when compared with matched adjacent normal tissues. In addition, DR6 enhanced ovarian carcinoma cell migration ability, and decreased expression of DR6 inhibited the expression of matrix metalloprotease (MMP) 2 and MMP9, and increased the expression of E-cadherin. Additionally, DR6 shRNA caused a significant decrease in phosphoinositide-3-kinase (PI3K), phospho (p) -AKT, p-extracellular signal-regulated kinase (ERK), and p-mitogen-activated protein kinase kinase expression in SKOV3 cells. These results suggested that DR6 can enhance ovarian carcinoma cell migration ability through the mitogen-activated protein kinase/ERK and PI3K/AKT pathways. Notably, mass spectrometric analysis indicated that DR6 co-purified with kinesin family member 11 (KIF11), and we verified the interaction between KIF11 and DR6 by co-immunoprecipitation and glutathione S-transferase pull-down. Furthermore, we demonstrated that DR6 can bind tumor necrosis factor receptor-associated factor 4 (TRAF4) with co-immunoprecipitation. Overexpression of KIF11 or TRAF4 eliminated the suppression of carcinoma cell migration by DR6 knockdown. We also found that TRAF4 and KIF11 were upregulated in ovarian carcinomas and that their level of expression was positively correlated with that of DR6. The findings above suggest that DR6 may play a notable oncogenic role in ovarian malignancy by interacting with TRAF4 and KIF11, and that DR6 may be an effective therapeutic target in ovarian cancer.

GALNT5 uaRNA promotes gastric cancer progression through its interaction with HSP90.

Recently, long noncoding RNAs (lncRNAs) have been reported to play a pivotal role in the occurrence and progression of cancer because of their unique characteristics and have therefore become an active area of cancer research. The object of this study was to screen lncRNAs that are dysregulated in gastric cancer and to investigate their potential functions. Global expression of lncRNAs in gastric cancer and adjacent normal tissues of patients was profiled using a microarray assay. We identified an lncRNA (GALNT5 uaRNA, UTR-associated RNA) that is derived from the 3'-UTR of GALNT5. This lncRNA was transcribed independently of the coding region of GALNT5 and was determined to be markedly upregulated in human gastric carcinoma relative to their corresponding normal gastric tissues by quantitative RT-PCR (qRT-PCR) analysis of tissues from 122 gastric carcinoma patients. The expression of GALNT5 uaRNA was significantly correlated with the TNM stage and with lymph node metastasis. Further results demonstrated that GALNT5 uaRNA facilitated the proliferation and migration of gastric cancer cells in vitro and promoted tumor growth in a mouse model of human gastric cancer. Our results also indicated that GALNT5 uaRNA might function in gastric cancer by binding with HSP90. Further studies indicated that the 5'-end stem-loop motifs of GALNT5 uaRNA promoted the binding of HSP90 and its client proteins, and thus inhibited ubiquitination of the clients. These results expanded our understanding of GALNT5 uaRNA as a new avenue for therapeutic intervention against gastric cancer progression.

Transcriptome Identified lncRNAs Associated with Renal Fibrosis in UUO Rat Model.

Renal fibrosis represents a final common outcome of many renal diseases and has attracted a great deal of attention. To better understand whether lncRNAs could be a player in this process or be a biomarker for renal fibrosis diagnosis, we compared transcriptome sequencing data on renal tissues and urine respectively between UUO (unilateral ureteral obstruction) and shamed (Sham) rat model. Numerous genes including lncRNAs with significant changes in their expression were identified. 24 lncRNAs were up-regulated and 79 lncRNAs were down-regulated in the renal tissues of the UUO rats. 625 lncRNAs were up-regulated and 177 lncRNAs were down-regulated in urines of the UUO rats. Among the lncRNAs upregulated in renal tissue of UUO rats, 19 lncRNAs were predicted containing several conserved Smad3 binding motifs in the promoter. Among them, lncRNAs with putative promoter containing more than 4 conserved Smad3 binding motifs were demonstrated to be induced by TGF-ß significantly in normal rat renal tubular epithelial NRK-52E cells. We further confirmed that lncRNA TCONS_00088786 and TCONS_01496394 were regulated by TGF-ß stimulation and also can influence the expression of some fibrosis-related genes through a feedback loop. Based on transcriptome sequencing data, bioinformatics analysis and qRT-PCR detection, we also demonstrated lncRNA in urine are detectable and might be a novel biomarker of renal fibrosis. These results provide new information for the involvement of lncRNAs in renal fibrosis, indicating that they may serve as candidate biomarkers or therapeutic targets in the future.

Functions of miR-146a and miR-222 in Tumor-associated Macrophages in Breast Cancer.

Tumor-associated macrophages (TAMs) play critical roles in promoting tumor progression and invasion. However, the molecular mechanisms underlying TAM regulation remain to be further investigated and may make significant contributions to cancer treatment. Mammalian microRNAs (miRNAs) have recently been identified as important regulators of gene expression that function by repressing specific target genes mainly at the post-transcriptional level. However, systematic studies of the functions and mechanisms of miRNAs in TAMs in tumor tissues are rare. In this study, miR-146a and miR-222 were shown to be significantly decreased in TAMs associated with the up-regulated NF-κB p50 subunit. miR-146a promoted the expression of some M2 macrophage phenotype molecules, and miR-146a antagomir transfected RAW264.7 monocyte-macrophage cells inhibited 4T1 tumor growth in vivo. Meanwhile, overexpression of miR-222 inhibited TAM chemotaxis, and miR-222 in TAMs inhibited 4T1 tumor growth by targeting CXCL12 and inhibiting CXCR4. These data revealed that miRNAs influence breast tumor growth by promoting the M2 type polarization or regulating the recruitment of TAMs. These observations suggest that endogenous miRNAs may exert an important role in controlling the polarization and function of TAMs in breast cancer.