A-kinase-interacting protein 1 promotes EMT and metastasis via PI3K/Akt/IKKβ pathway in cervical cancer.

Overexpression of A-kinase-interacting protein 1 (AKIP1) has been reported in prostate and breast cancers. Nevertheless, the clinical potential of AKIP1 during the development of cervical cancer (CC) remains unclear. A series of experiments involving BdU, colony formation, wound healing and cell invasion assays were performed to determine cell proliferation, migration and invasion, respectively. Gene expression changes were validated by qRT-PCR, Western blotting and immunocytochemistry. We found that AKIP1 expression is increased in CC cell lines and tissue specimens from CC patients. The elevated AKIP1 expression in primary tumours was related to lymph node metastasis in CC patients. In addition, we observed that overexpression of AKIP1 promotes CC cell proliferation. Enhanced expression of AKIP1 facilitated the migration and invasion of CC cells by inducing NF-κB-dependent epithelial-mesenchymal transition (EMT). Moreover, mechanistic investigations revealed that AKIP1 induced nuclear translocation and phosphorylation of the p65 NF-κB subunit through the PI3K/Akt/IKKβ pathway. Conversely, enhanced expression of phosphatase and tensin homologue (PTEN) inhibited this signalling pathway and restored an epithelial phenotype to CC cells in the presence of overexpressed AKIP1. Our results indicate that AKIP1 promotes the EMT and metastasis in CC by activating NF-κB signalling through the PI3K/Akt/IKKβ pathway, suggesting that AKIP1 could be a pivotal regulator of an EMT axis in CC. SIGNIFICANCE OF THE STUDY: AKIP1 expression in the samples of CC patients and in in vitro tumour cell lines provides evidence that expression of AKIP1 in CC contributes to cancer progression. Our findings indicate that AKIP1 promotes the epithelial-mesenchymal transition and metastasis in CC by activating NF-κB signalling through the PI3K/Akt/IKKβ pathway, suggesting that AKIP1 is a pivotal regulator of an EMT axis in CC. AKIP1 could be implicated as a potential therapeutic target as well as a valuable biomarker for evaluating prognosis for patients with CC.

Zhang X ，Liu S ，Zhu Y 《-》

A-kinase-interacting protein 1 facilitates growth and metastasis of gastric cancer cells via Slug-induced epithelial-mesenchymal transition.

A-kinase-interacting protein 1 (AKIP1) has previously been reported to act as a potential oncogenic protein in various cancers. The clinical significance and biological role of AKIP1 in gastric cancer (GC) is, however, still elusive. Herein, this study aimed to investigate the functional and molecular mechanism by which AKIP1 influences GC. AKIP1 mRNA and protein expressions in GC tissues were examined by quantitative real-time PCR (qRT-PCR), Western blot and immunohistochemistry. Other methods including stably transfected against AKIP1 into gastric cancer cells, wound healing, transwell assays, CCK-8, colony formation, qRT-PCR and Western blot in vitro and tumorigenesis in vivo were also performed. The up-regulated expression of AKIP1 in GC specimens significantly correlated with clinical metastasis and poor prognosis in patients with GC. AKIP1 knockdown markedly suppressed GC cells proliferation, invasion and metastasis both in vitro and in vivo. In contrast, AKIP1 overexpression resulted in the opposite effects. Moreover, mechanistic analyses indicated that Slug-induced epithelial-mesenchymal transition (EMT) might be responsible for AKIP1-influenced GC cells behaviour. Our findings demonstrated that high AKIP1 expression significantly correlated with clinical metastasis and unfavourable prognosis in patients with GC. Additionally, AKIP1 promoted GC cells proliferation, migration and invasion by activating Slug-induced EMT.

Chen D ，Cao G ，Liu Q 《-》

RPS15A promotes gastric cancer progression via activation of the Akt/IKK-β/NF-κB signalling pathway.

This study aimed to investigate the clinical significance, potential biological function and underlying mechanism of RPS15A in gastric cancer (GC) progression. RPS15A expression was detected in 40 pairs of GC tissues and matched normal gastric mucosae (MNGM) using qRT-PCR analysis. Immunohistochemistry assay was conducted using a tissue microarray including 186 primary GC samples to characterize the clinical significance of RPS15A. A series of in vitro and in vivo assays were performed to elucidate the biological function of RPS15A in GC development and underlying molecular mechanisms. The expression of RPS15A was significantly up-regulated in GC samples compared to MNGM, and its expression was closely related to TNM stage, tumour size, differentiation, lymph node metastasis and poor patient survival. Ectopic expression of RPS15A markedly enhanced the proliferation and metastasis of GC cells both in vitro and in vivo. RPS15A overexpression also promoted the epithelial-mesenchymal transition (EMT) phenotype formation of GC cells. Investigations of underlying mechanisms found that RPS15A activated the NF-κB signalling pathway by inducing the nuclear translocation and phosphorylation of the p65 NF-κB subunit, transactivation of NF-κB reporter and up-regulating target genes of this pathway. In addition, RPS15A overexpression activated, while RPS15A knockdown inhibited the Akt/IKK-β signalling axis in GC cells. And both Akt inhibitor LY294002 and IKK inhibitor Bay117082 neutralized the p65 and p-p65 nuclear translocation induced by RPS15A overexpression. Collectively, our findings suggest that RPS15A activates the NF-κB pathway through Akt/IKK-β signalling axis, and consequently promotes EMT and GC metastasis. This newly identified RPS15A/Akt/IKK-β/NF-κB signalling pathway may be a potential therapeutic target to prevent GC progression.

Liu C ，He X ，Liu X ，Yu J ，Zhang M ，Yu F ，Wang Y ... -  《-》

LncRNA LINC01305 silencing inhibits cell epithelial-mesenchymal transition in cervical cancer by inhibiting TNXB-mediated PI3K/Akt signalling pathway.

Cervical cancer (CC) remains one of the leading malignancies afflicting females worldwide, with its aetiology associated with long-term papillomavirus infection. Recent studies have shifted their focus and research attention to the relationship between long non-coding RNAs (lncRNAs) and CC therapeutic. Thus, the aim of the current study was to investigate the underlying mechanism of lncRNA LINC01305 on the cell invasion, migration and epithelial-mesenchymal transition (EMT) of CC cells via modulation of the PI3K/Akt signalling pathway by targeting tenascin-X B (TNXB). The expressions of LINC01305, TNXB, MMP2, MMP9, E-cadherin, vimentin, PI3K, Akt, p-PI3K, p-Akt and TNXB were detected in this study. After which, the cell invasion and migration abilities of the CC cells were determined respectively. Bioinformatics and the application of a dual luciferase reporter gene assay provided verification indicating that TNXB is the target gene of lncRNA LINC01305. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis methods revealed that the expressions of MMP2, MMP9, vimentin, PI3K, Akt, p-PI3K and p-Akt were decreased following the down-regulation of LncRNA LINC01305 or overexpression of TNXB. LncRNA LINC01305 silencing or TNXB overexpression was noted to decrease the migration and invasion of SiHa cells. Taken together, the key findings of the current study present evidence suggesting that lncRNA LINC01305 silencing suppresses EMT, invasion and migration via repressing the PI3K/Akt signalling pathway by means of targeting TNXB in CC cells, which ultimately provides novel insight and identification of potential therapeutic targets for CC.

Yan SP ，Chu DX ，Qiu HF ，Xie Y ，Wang CF ，Zhang JY ，Li WC ，Guo RX ... -  《-》

F-box protein FBXO31 modulates apoptosis and epithelial-mesenchymal transition of cervical cancer via inactivation of the PI3K/AKT-mediated MDM2/p53 axis.

Cervical cancer (CC) is one of the most common malignant tumours in the world and a serious threat to women's health. The dysregulation of protein degradation mediated by F-box proteins is involved in tumorigenesis, and F-box protein FBXO31 has been reported to play an important role in various human cancers. However, the role of FBXO31 in CC remains unclear. This study aimed to investigate the function and underlying regulatory mechanism of FBXO31 in CC. In this study, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were used to measure target gene expression; the Cell Counting Kit-8, cell death ELISA, Transwell invasion assay, wound-healing assay and western blot were applied to assess cell viability, apoptosis, invasion, migration and epithelial-mesenchymal transition (EMT), respectively. FBXO31 was expressed at a low level in 37 pairs of CC tissues and three types of CC cell lines. Overexpression of FBXO31 inhibited cell viability, invasion, migration, EMT and induced apoptosis in SiHa cells. FBXO31 promoted p53 activity through suppression of murine double minute 2 (MDM2) expression. Overexpression of MDM2 ameliorated the inhibitory effect of FBXO31 on SiHa cells, while the MDM2/p53 axis-specific inhibitor Nutlin-3a facilitated this inhibitory effect. Further, we confirmed that FBXO31 inactivated MDM2/p53 axis dependence on the phospholipid inositol 3-kinase (PI3K)/protein kinase B (AKT) signalling pathway. Collectively, our results reveal that FBXO31 down-regulates CC progression by blocking the PI3K/AKT-mediated MDM2/p53 axis, suggesting that FBXO31 may serve as a promising therapeutic target for CC treatment.

Liu K ，Xue B ，Bai G ，Zhang W ... -  《-》