Knockdown of STIL suppresses the progression of gastric cancer by down-regulating the IGF-1/PI3K/AKT pathway.

SCL/TAL1 interrupting locus (STIL) regulates the mitotic centrosome to promote the centriolar replication and cell cycling, and is associated with malignancies. However, the role and mechanism of STIL in gastric cancer (GC) remain elusive. STIL expression in GC tissue microarray was detected by immunohistochemistry (IHC). GC cells were transduced with control lentivirus or lentivirus for expression STIL-specific shRNA and the effect of STIL silencing on the malignant behaviors of GC cells was measured in vitro and in vivo. The potential mechanisms underlying the action of STIL were analyzed by transcriptome microarray and bioinformatics. STIL expression was up-regulated in GC tissues both in our cohort and the data from the cancer genome atlas, and positively associated with T stage and poor overall survival of GC patients. Knockdown of STIL significantly inhibited the proliferation and clonogenicity of human GC cells and attenuated the growth of implanted GC in vivo. Furthermore, STIL silencing induced cell cycle arrest in G2/M phase and apoptosis of GC cells. Transcriptome analysis indicated that STIL silencing modulated many gene expression, particularly for down-regulating the IGF-1/PI3K/AKT pathway. In addition, treatment with SC79, an AKT activator, significantly mitigated the effect of STIL-silencing in GC cells. In conclusion, STIL promotes gastric carcinogenesis and progression by enhancing the IGF-1/PI3K/AKT signaling, and STIL may be a novel target for intervention of GC.

Wang J ，Zhang Y ，Dou Z ，Jiang H ，Wang Y ，Gao X ，Xin X ... -  《-》

NUCKS1 promotes gastric cancer cell aggressiveness by upregulating IGF-1R and subsequently activating the PI3K/Akt/mTOR signaling pathway.

The effects of nuclear ubiquitous casein and cyclin-dependent kinase substrate 1 (NUCKS1) on tumor cells and the relevant mechanisms are less well defined. This study aimed to explore the role and mechanism of action of NUCKS1 in gastric cancer (GC) progression. The expression dynamics of NUCKS1 were examined using microarray-based immunohistochemistry (IHC) in a group of carcinomatous and adjacent non-tumor specimens. Various in vitro and in vivo assays were performed to clarify the function of NUCKS1 in GC and its underlying mechanisms. In our research, NUCKS1 overexpression was identified by IHC in 86/200 (43%) GC patients, was significantly related to the invasive phenotype of GC and was an indisputable predictor of shortened survival. Depleting NUCKS1 in GC cells significantly induced apoptosis and reduced cell proliferation and invasiveness in vitro and inhibited tumor growth in vivo. Additionally, ectopic overexpression of NUCKS1 in GC cells enhanced proliferation and invasion in vitro and promoted tumor growth in vivo. Importantly, PI3K/Akt/mTOR signaling pathway activity was inhibited upon downregulation of NUCKS1 expression and enhanced by ectopic overexpression of NUCKS1. Subsequently, the insulin-like growth factor 1 receptor (IGF-1R) gene was found to be a potential downstream target of NUCKS1 in GC cells, and knockdown of IGF-1R eliminated the augmentation of GC cell migration, invasion and proliferation as well as PI3K/Akt/mTOR signaling pathway activity by ectopic NUCKS1. The data suggested that NUCKS1 enhanced GC aggressiveness via the PI3K/Akt/mTOR signaling pathway in an IGF-1R-dependent manner. NUCKS1 or its respective signaling pathways could hold immense promise as potent anticancer targets for GC treatment.

Huang YK ，Kang WM ，Ma ZQ ，Liu YQ ，Zhou L ，Yu JC ... -  《-》

Targeting of SPP1 by microRNA-340 inhibits gastric cancer cell epithelial-mesenchymal transition through inhibition of the PI3K/AKT signaling pathway.

Gastric cancer (GC) is a common heterogeneous disease. The critical roles of microRNA-340 (miR-340) in the development and progression of GC were emphasized in accumulating studies. This study aims to examine the regulatory mechanism of miR-340 in GC cellular processes. Initially, microarray technology was used to identify differentially expressed genes and regulatory miRs in GC. After that, the potential role of miR-340 in GC was determined via ectopic expression, depletion, and reporter assay experiments. Expression of secreted phosphoprotein 1 (SPP1), miR-340, phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, and epithelial-mesenchymal transition (EMT)-related genes was measured. Moreover, to further explore the function of miR-340 in vivo and in vitro, proliferation, apoptosis, migration, invasion, and tumorigenic capacity were evaluated. SPP1 was a target gene of miR-340 which could then mediate the PI3K/AKT signaling pathway by targeting SPP1 in GC. Furthermore, miR-340 levels were reduced and SPP1 was enriched in GC tissues and cells, with the PI3K/AKT signaling pathway being activated. Inhibitory effects of upregulated miR-340 on SPP1 and the PI3K/AKT signaling pathway were confirmed in vivo and in vitro. Overexpression of miR-340 or the silencing of SPP1 inhibited GC cell proliferation, invasion, migration, and EMT process, but promoted apoptosis of GC cells. Typically, targeting of SPP1 by miR-340 may contribute to the inhibition of proliferation, migration, invasion, and EMT of GC cells via suppression of PI3K/AKT signaling pathway.

Song SZ ，Lin S ，Liu JN ，Zhang MB ，Du YT ，Zhang DD ，Xu WH ，Wang HB ... -  《-》

The human oncogene SCL/TAL1 interrupting locus (STIL) promotes tumor growth through MAPK/ERK, PI3K/Akt and AMPK pathways in prostate cancer.

The morbidity and mortality of prostate cancer (PCa) in China have increased obviously, which became the second leading cause of death in men with cancer. Hedgehog (Hh) signaling pathway is a key signaling pathway involved in the prostate cancer progression. The human oncogene SCL/TAL1 interrupting locus (STIL) can modulate the Hh signaling pathway, but its function in PCa has not been reported. Here, we showed that STIL was increased in high grade prostate cancer tissue. Knockdown of STIL in prostate cancer cells PC-3 and DU 145 significantly decreased the proliferation of cells and induced cellular apoptosis through casepase3/7 mediated pathway. Moreover, the colony formation ability was also inhibited when knockdown of STIL by lentivirus-mediated shRNA. Furthermore, the cellular signaling antibody array analysis revealed which signaling pathway was affected when silencing STIL. Altogether, we found that STIL could affect MAPK/ERK, PI3K/Akt and AMPK signaling pathways, thus promoting cellular proliferation, colony formation and suppressing cellular apoptosis in prostate cancer.

Wu X ，Xiao Y ，Yan W ，Ji Z ，Zheng G ... -  《-》

Mir-20a-5p induced WTX deficiency promotes gastric cancer progressions through regulating PI3K/AKT signaling pathway.

Li J ，Ye D ，Shen P ，Liu X ，Zhou P ，Zhu G ，Xu Y ，Fu Y ，Li X ，Sun J ，Xu J ，Zhang Q ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》