Klotho suppresses tumor progression via inhibiting PI3K/Akt/GSK3β/Snail signaling in renal cell carcinoma.

Klotho is an anti-aging protein predominantly expressed in renal tubular epithelial cells. Although Klotho was recently identified as a tumor suppressor gene in a variety of cancers, the potential role and molecular events for Klotho in renal cell carcinoma (RCC) remain obscure. In the present study, immunohistochemical staining in tissue microarrays containing 125 RCC samples showed that intratumoral Klotho levels were negatively correlated with tumor size, TNM stage and nuclear grade. The overall survival rate of RCC patients with high Klotho expression was significantly higher than that of patients with low Klotho expression. Functional analysis after gain and loss of Klotho expression revealed that Klotho blunted epithelial-mesenchymal transition and cellular migration and invasion in RCC. Also, no alteration of α-2,6-sialidase activity was found after Klotho overexpression in RCC. The molecular signals for this phenomenon involved the Klotho-mediated inhibition of PI3K/Akt/GSK3β/Snail pathway. Importantly, compared to localized RCC tissues, advanced RCC tissues exhibited low Klotho expression accompanied with high pAkt and Snail expression. These results indicate Klotho acts as a tumor suppressor by inhibiting PI3K/Akt/GSK3β/Snail signaling, thus suppressing epithelial-mesenchymal transition and tumor migration and invasion during RCC progression. As a result, Klotho might be used as a potential therapy for advanced RCC.

Zhu Y ，Xu L ，Zhang J ，Xu W ，Liu Y ，Yin H ，Lv T ，An H ，Liu L ，He H ，Zhang H ，Liu J ，Xu J ，Lin Z ... -  《-》

Acylglycerol kinase promotes tumour growth and metastasis via activating the PI3K/AKT/GSK3β signalling pathway in renal cell carcinoma.

Zhu Q ，Zhong AL ，Hu H ，Zhao JJ ，Weng DS ，Tang Y ，Pan QZ ，Zhou ZQ ，Song MJ ，Yang JY ，He JY ，Liu Y ，Li M ，Hu WM ，Yang CP ，Xiang T ，Chen MY ，Ma G ，Guo L ，Xia JC ... -  《Journal of Hematology & Oncology》

CEP55 promotes epithelial-mesenchymal transition in renal cell carcinoma through PI3K/AKT/mTOR pathway.

Chen H ，Zhu D ，Zheng Z ，Cai Y ，Chen Z ，Xie W ... -  《-》

Transmembrane-Bound IL-15-Promoted Epithelial-Mesenchymal Transition in Renal Cancer Cells Requires the Src-Dependent Akt/GSK-3β/β-Catenin Pathway.

Intrarenal interleukin-15 (IL-15) plays a major role controlling epithelial survival and polarization both in physiological and pathologic conditions. Herein, we confirmed that human renal cell carcinomas (RCCs) express a membrane-bound IL-15 isoform displaying an unusual molecular weight of 27 kDa. Its stimulation with soluble IL-15 receptor α chain (s-IL-15Rα) triggers epithelial-mesenchymal transition (EMT) process as shown by the down-regulation of E-cadherin and zona occludens 1 and the up-regulation of vimentin and N-cadherin and promotes the migratory and invasive properties of RCC. S-IL-15Rα treatment triggered the Src/PI3K/Akt/GSK-3β pathway and promoted β-catenin nuclei translocation. Deactivation of this pathway by using Src-specific inhibitor PP2, PI3K inhibitor LY294002, and AKT inhibitor MK2206 hampered β-catenin nuclei translocation and suppressed EMT, migration, and invasion of RCC. S-IL-15Rα treatment also enhanced Src-dependent phosphorylation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (Erk1/2). FAK knockdown significantly decreased the migration and invasion of RCC, which suggest that Src-FAK signaling was involved in s-IL-15Rα-favored migration and invasion of RCC. At the same time, inhibitors of Erk1/2 also significantly decreased the migration and invasion of RCC but could not reverse s-IL-15Rα-induced EMT. Taken together, our results reveal that Src-dependent PI3K/Akt/GSK3b/β-catenin pathway is required for s-IL-15Ra-dependent induction of EMT in RCC, while Src-FAK and Src-Erk1/2 signaling were involved in s-IL-15Rα-promoted migration and invasion properties of RCC. Our study provides a better understanding of IL-15 signaling in RCC tumor progression, which may lead to novel targeted therapies and provide some suggestions when using IL-15 in clinic.

Yuan H ，Meng X ，Guo W ，Cai P ，Li W ，Li Q ，Wang W ，Sun Y ，Xu Q ，Gu Y ... -  《NEOPLASIA》

Ghrelin promotes renal cell carcinoma metastasis via Snail activation and is associated with poor prognosis.

Ghrelin is an appetite-regulating molecule that promotes growth hormone (GH) release and food intake through growth hormone secretagogue receptor (GHS-R). Recently, high ghrelin levels have been detected in various types of human cancer. Ghrelin expression is observed in proximal and distal renal tubules, where renal cell carcinoma (RCC) arises. However, whether ghrelin is up-regulated and promotes renal cell carcinogenesis remains obscure. In this study, we observed that ghrelin was highly expressed in renal tumours, especially in metastatic RCC. In addition, high ghrelin levels correlated with poor outcome, lymph node and distant metastasis. The addition of ghrelin promoted the migration ability of RCC cell lines 786-0, ACHN and A-498. Furthermore, knockdown of ghrelin expression reduced in vitro migration and in vivo metastasis, suggesting a requirement for ghrelin accumulation in the microenvironment for RCC metastasis. Analysis of microarray signatures using Ingenuity Pathway Analysis (IPA) and MetaCore pointed to the potential regulation by ghrelin of Snail, a transcriptional repressor of E-cadherin. We further observed that Ghrelin increased the expression, nuclear translocation and promoter-binding activity of Snail. Snail silencing blocked the ghrelin-mediated effects on E-cadherin repression and cell migration. Snail-E-cadherin regulation was mediated by GHS-R-triggered Akt phosphorylation at Ser473 and Thr308. Pretreatment with PI3K inhibitors, LY294002 and wortmannin, as well as Akt siRNA, decreased ghrelin-induced Akt phosphorylation, Snail promoter binding activity and migration. Taken together, our findings indicate that ghrelin can activate Snail function via the GHS-R-PI3K-Akt axis, which may contribute to RCC metastasis. The microarray raw data were retrieved from the Cancer Genome Atlas (TCGA) [KIRC gene expression (IlluminaHiSeq) dataset].

Lin TC ，Liu YP ，Chan YC ，Su CY ，Lin YF ，Hsu SL ，Yang CS ，Hsiao M ... -  《-》