Inhibitor of growth 4 inhibits cell proliferation, migration, and induces apoptosis of renal cell carcinoma cells.

The inhibitor of growth 4 (ING4) is known as a tumor suppressor. The expressions of ING4 were markedly reduced in human renal clear cell carcinoma (ccRCC) tissues. However, the role of ING4 in renal cell carcinoma (RCC) remains unknown. The aim of the current study was to detect the ING4 expression level and its potential role in human RCC cell lines. Our results showed that ING4 was lowly expressed in human RCC cell lines compared with that in proximal tubular cell line. Ectopic overexpression of ING4 inhibited the proliferation, migration, and invasion properties, and as well as prevented epithelial-mesenchymal transition (EMT) phenotype of RCC cells. In addition, ING4 overexpression induced cell apoptosis and autophagy in RCC cells. Furthermore, ING4 overexpression suppressed the activation of PI3K/Akt pathway in RCC cells. The activator of PI3K/Akt, insulin-like growth factor 1, abolished the effects of ING4 on RCC cells. These findings indicated that ING4 presented anticancer activity in RCC cells. The effects of ING4 on RCC cells were mediated by regulating the PI3K/Akt pathway. These findings suggested that ING4 could be used for gene therapy of RCC.

Sun J ，Xie L ，Lv J ，Zhang W ，Lv J ，Liang Y ，Geng Y ，Li X ... -  《-》

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 ... -  《-》

Tuftelin 1 (TUFT1) Promotes the Proliferation and Migration of Renal Cell Carcinoma via PI3K/AKT Signaling Pathway.

Tuftelin 1 (TUFT1), a protein functioning distinctively in different tissues, is reported to be elevated in several types of cancers and the elevation of TUFT1 is correlated with unfavorable clinicopathologic characteristics and poor survival. However, the involvement of TUFT1 in renal cell carcinoma (RCC) remains unknown. In the current study, we investigated the role of TUFT1 in RCC and potential underlying mechanisms. RT-PCR and Western blot analysis showed that both the mRNA and protein levels of TUFT1 were increased in primary RCC tissue and RCC cell lines. TUFT1 overexpression in RCC cells resulted in enhanced cell proliferation and migration while knockdown of TUFT1 by contrast decreased the growth and migration of the RCC cells, indicating TUFT1 expression is involved in RCC cell growth and migration. The involvement of TUFT1 in the epithelial-mesenchymal transition (EMT) of RCC cells was also determined by measuring the expression of EMT-related markers. Our data showed that TUFT1 overexpression promoted RCC cell EMT progression while knockdown of TUFT1 suppressed such process. Further signaling pathway inhibition assay revealed that TUFT1-induced RCC cell growth, migration and EMT was significantly suppressed by PI3K inhibitor, but not JNK or MEK inhibitors. In addition, TUFT1 overexpression enhanced the AKT phosphorylation, a key member of the PI3K signaling pathway, while PI3K inhibitor suppressed such process. Taken together, our study showed that TUFT1 expression was elevated in RCC and such elevation promoted the proliferation, migration and EMT of RCC cells in vitro, through PI3K/AKT signaling pathway. The findings of our current study imply that TUFT1 is involved in RCC tumorigenesis, and it may serve as a biomarker for RCC diagnosis and a potential target for RCC treatment.

Lin H ，Zeng W ，Lei Y ，Chen D ，Nie Z ... -  《-》

Low expression of PDK1 inhibits renal cell carcinoma cell proliferation, migration, invasion and epithelial mesenchymal transition through inhibition of the PI3K-PDK1-Akt pathway.

As the most commonly occurring form of primary renal tumor, renal cell carcinoma (RCC) is a malignancy accompanied by a high mortality rate. 3-phosphoinositide-dependent protein kinase 1 (PDK1) has been established as a protein target and generated considerable interest in both the pharmaceutical and academia industry. The aim of the current study was to investigate the effect of si-PDK1 on the RCC cell apoptosis, proliferation, migration, invasion and epithelial mesenchymal transition (EMT) in connection with the PI3K-PDK1-Akt pathway. Microarray analysis from the GEO database was adopted to identify differentially expressed genes (DEGs) related to RCC, after which the positive expression of the PDK1 protein in tissue was determined accordingly. The optimal silencing si-RNA was subsequently selected and RCC cell lines 786-O and A498 were selected and transfected with either a si-PDK1 or activator of the PI3K-PDK1-Akt pathway for grouping purposes. The mRNA and protein expressions of PDK1, the PI3K-PDK1-Akt pathway-, EMT- and apoptosis-related genes were then evaluated. The effect of si-PDK1 on cell proliferation, apoptosis, invasion and migration was then analyzed. Through microarray analysis of GSE6344, GSE53757, GSE14762 and GSE781, PDK1 was examined. PDK1 was determined to be highly expressed in RCC tissues. Si-PDK1 exhibited marked reductions in relation to the mRNA and protein expression of PDK1, PI3K, AKT as well as Vimentin while elevated mRNA and protein expressions of E-cadherin were detected, which ultimately suggested that cell migration, proliferation and invasion had been inhibited coupled with enhanced levels of cell apoptosis. While a notable observation was made highlighting that the PI3K-PDK1-Akt pathway antagonized the effect of PDK1 silencing. Taken together, the key observations of this study provide evidence suggesting that high expressions of PDK1 are found in RCC, while highlighting that silencing PDK1 could inhibit RCC cell proliferation, migration, invasion and EMT by repressing the PI3K-PDK1-Akt pathway.

Zhou WM ，Wu GL ，Huang J ，Li JG ，Hao C ，He QM ，Chen XD ，Wang GX ，Tu XH ... -  《-》

Exosomal microRNA-15a from ACHN cells aggravates clear cell renal cell carcinoma via the BTG2/PI3K/AKT axis.

Accumulating studies have indicated that exosomal microRNAs (miRNAs/miRs) can mediate clear cell renal cell carcinoma (ccRCC) at the early stage, but the mechanisms remain to be specified. Here, we investigated the mechanism of exosomal miR-15a in ccRCC. After successful isolation of exosomes from RCC cells, we found that miR-15a was upregulated in ccRCC cells. Moreover, upregulation of miR-15a by pre-miR-15a promoted the proliferation, migration, invasion, and epithelial-mesenchymal transition of ccRCC cells. A luciferase assay revealed that B-cell translocation gene 2 (BTG2) was a target gene of miR-15a and negatively correlated with miR-15a expression. BTG2 was poorly expressed in ccRCC, which reduced the proliferation of ccRCC cells. In addition, overexpression of BTG2 could reverse the promotive effects of miR-15a on ccRCC. Furthermore, BTG2 reduced PI3K/AKT pathway activity. Our results collectively indicated that exosomal miR-15a from RCC cells accelerated cell viability by downregulating BTG2 and promoting the activity of the PI3K/AKT signaling pathway. We demonstrated a novel mechanism by which exosomal miR-15a exerted pro-proliferatory effects on ccRCC, highlighting the potential of exosomal miR-15a as a target for ccRCC prognosis.

Li DY ，Lin FF ，Li GP ，Zeng FC ... -  《-》