TRIM11 promotes tumor angiogenesis via activation of STAT3/VEGFA signaling in lung adenocarcinoma.

Tripartite motif containing 11 (TRIM11) plays important roles in the regulation of lung cancer behaviors. However, the mechanisms of action of TRIM11 in tumor angiogenesis remain unclear. In this study, we found that TRIM11 expression is higher in lung adenocarcinoma (ADC) than in normal lung tissues. High TRIM11 expression was found to be associated with advanced progression and a poor prognosis of lung ADCs. Functional assays demonstrated that TRIM11 promoted tumor growth and angiogenesis in vivo and enhanced migration of (and tube formation by) human umbilical vein endothelial cells (HUVECs). Mechanistically, TRIM11 was found to regulate angiogenesis through the signal transducer and activator of transcription 3 (STAT3)/vascular endothelial growth factor A (VEGFA) pathway. Moreover, in clinical samples, VEGFA expression was much higher in cancer tissue samples and positively correlated with TRIM11 expression. TRIM11-overexpressing samples showed higher CD31 staining and microvessel density. Thus, we provide evidence that TRIM11 is a proangiogenic factor in lung ADC and may serve as a therapeutic target for lung ADC treatment.

NES1/KLK10 promotes trastuzumab resistance via activation of PI3K/AKT signaling pathway in gastric cancer.

Trastuzumab, a humanized antibody targeting human epidermal growth factor receptor 2 (HER2), exhibits remarkable therapeutic efficacy against HER2-positive gastric cancer. Acquired resistance to trastuzumab remains a barrier to patient survival and the mechanisms underlying this are still not well understood. The normal epithelial cell-specific-1 (NES1) gene, also named as KLK10, is recognized as a potential therapeutic target for reversing trastuzumab resistance. The aim of this study was to explore the potential role of KLK10 in trastuzumab resistance (TR) gastric cancer cells. We found that KLK10 was significantly upregulated in trastuzumab-resistant cell lines, SGC7901-TR and BGC-823-TR. In addition, down regulation of KLK10 reversed the resistance in trastuzumab resistant cells. Overexpression of KLK10 induced trastuzumab resistance, and activated the PI3K/AKT signaling pathway, while downregulation of KLK10 presented the opposite effects. Moreover, when the PI3K/AKT signaling pathway was inhibited, the effect of KLK10 on resistance was diminished. Furthermore, combination of trastuzumab and PI3K/AKT inhibitor XL147 effectively inhibited tumor growth in KLK10-overexpressing xenografts. Taken together, our findings show that KLK10 promotes trastuzumab resistance, at least in part, through the PI3K/AKT signaling pathway, suggesting that KLK10 is a potentially target to overcome trastuzumab resistance, and the combination might overcome trastuzumab resistance in KLK10-overexpressed gastric cancer patients.