Preclinical Evidence that Arctigenin Effectively and Selectively Targets Clear Cell Renal Cell Carcinoma Via Suppressing EGFR and RhoA.

Clear cell renal cell carcinoma (ccRCC) has poor clinical outcomes and necessitates new treatment options. Epidermal growth factor receptor (EGFR) is a potential therapeutic target, due to the associations with various carcinomas' progression. Arctigenin, a natural compound of Arctium lappa, has been shown to display anticancer abilities in various carcinomas. Cellular assays and combination studies were conducted using arctigenin and anti-ccRCC drugs. In vivo efficacy of arctigenin was determined using ccRCC xenograft mouse model. Immunoblotting and biochemistry analysis were applied to investigate the signaling affected by arctigenin. Arctigenin inhibits growth, migration, and survival of ccRCC cells while sparing normal kidney cells. Arctigenin acts synergistically with 5-FU and sorafenib but not temsirolimus in inhibiting ccRCC cells. Synergism of arctigenin with 5-FU and sorafenib was further shown in ccRCC xenograft mouse model. The combination of arctigenin with clinical anti-RCC drugs completely inhibits tumor growth without tumor progression even for an extended time period. Mechanistically, arctigenin inhibits migration in a RhoA-dependent manner while inhibits growth via suppressing EGFR-mediated signaling pathways. Our findings suggest that arctigenin performs well to add to current treatment in ccRCC and confirm the value to target EGFR to improve therapy in RCC.

Downregulation of Transmembrane protein 40 by miR-138-5p Suppresses Cell Proliferation and Mobility in Clear Cell Renal Cell Carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) represents approximately 70% of RCC,as the most frequent histological subtype of RCC. MiR-138-5p, a tumor-related microRNA (miRNA), has been reported to be implicated in the diverse types of human malignancies, but its role in ccRCCremains unclear. OBJECTIVE: The study was designed to investigate the functional behaviors and regulatory mechanisms of miR-138-5p in ccRCC. MATERIALS AND METHODS: Quantitative real-time PCR and western blotting analyses were performed to determine the expression of miR-138-5p and TMEM40 in ccRCC tissues. Pearson's correlation coefficient was utilized to evaluate the correlation between miR-138-5p and TMEM40 expression. The function of miR-138-5p and TMEM40 in the cell proliferation, migration and invasion of ccRCC cells (786-O and ACHN) was assessed by CCK-8, colony formation, wound healing and transwell assay, respectively. A luciferase reporter assay was performed to confirm the direct binding of miR-138-5p to the target gene TMEM40. RESULTS: We found the expression of miR-138-5p was significantly down-regulated, while TMEM40 was remarkably up-regulated in ccRCC tissues. TMEM40 expression was discovered to be inversely correlated with miR-138-5p expression in ccRCC tissues. Functional studies demonstrated that miR-138-5p overexpression or TMEM40 knockdown significantly suppressed ccRCC cell proliferation, migration and invasion in vitro. Notably, we experimentally confirmed that miR-138-5p directly recognizes the 3'-UTR of the TMEM40 transcript and down-regulated its expression in ccRCC cells. CONCLUSIONS: Taken together, our findings provide the first clues regarding the role of miR-138-5p as a tumor suppressor in ccRCC by directly targeting of TMEM40.

Chrysin protects against renal ischemia reperfusion induced tubular cell apoptosis and inflammation in mice.

Renal ischemia reperfusion (IR) is a major cause of acute kidney injury with no effective treatment. Chrysin is an anti-inflammatory, anti-oxidant and anti-cancer agent. However, the effect of chrysin on renal IR injury remains unknown. In this study, sham operation, IR and IR+chrysin group mice were treated with or without renal IR injury. For renal IR, bilateral renal pedicles were clamped for 30 min and then released for 48 h of reperfusion. Blood and kidney samples were collected for analysis. Results demonstrated that chrysin pretreatment remarkably decreased the levels of serum creatinine and blood urea nitrogen and attenuated morphological abnormalities in renal IR injury. Consistently, tubular cell apoptosis and inflammation were more attenuated in the chrysin pretreatment group compared with the IR group. Chrysin pretreatment decreased the expression of Bax and cleaved caspase-3 and increased the expression of Bcl-2 in renal IR injury. Furthermore, chrysin administration decreased the mRNA and protein levels of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6. Furthermore, the IκBα/nuclear factor-κB signaling pathway was more suppressed in the chrysin pretreatment group compared with the IR group. In conclusion, chrysin protects against tubular cell apoptosis and inflammation in renal IR injury.