CLEC5A promotes the proliferation of gastric cancer cells by activating the PI3K/AKT/mTOR pathway.

Gastric cancer (GC), as one of the most prevalent malignancies, contributes to the high morbidity and mortality worldwide. By analyzing the bioinformatics, qRT-PCR and IHC assays, we found that CLEC5A is overexpressed in GC and associated with poorer prognosis. CLEC5A silencing inhibits cell growth and DNA replication and induces cell cycle arrest and cell apoptosis. Bioinformatics analyses and Western blotting revealed that CLEC5A depletion led to the dysregulation of the PI3K/AKT/mTOR pathway. CLEC5A-mediated GC proliferation and anti-apoptosis were impaired by blocking the PI3K/AKT/mTOR pathway with LY294002. We hypothesize that CLEC5A is of vital importance to GC initiation and progression via the PI3K/AKT/mTOR pathway, and that our results might represent promising therapeutic strategies for GC patients.

Wang Q ，Shi M ，Sun S ，Zhou Q ，Ding L ，Jiang C ，Bian T ，Jia F ，Liu Y ，Qin J ... -  《-》

C-type lectin domain family 5, member A (CLEC5A, MDL-1) promotes brain glioblastoma tumorigenesis by regulating PI3K/Akt signalling.

Glioblastoma is the most common malignant glioma of all brain tumours. It is difficult to treat because of its poor response to chemotherapy and radiotherapy and high recurrence rate after treatment. The aetiology of glioblastoma is a result of disorders of multiple factors. Depending on cell signal transduction, these glioblastoma-associated factors lead to cell proliferation, differentiation and apoptosis. Therefore, investigation of the potential factors which involved in the development of glioblastoma could provide a new target for the treatment of glioblastoma. We analysed the transcript expression of CLEC5A in glioblastoma by accessing The Cancer Genome Atlas (TCGA). qRT-PCR was performed to detect the RNA expression of genes in cells and tissues, and Western blot was used to measure the protein levels (Cyclin D1, Bcl-2, BAX, PCNA, MMP2, MMP9, Akt and Akt phosphorylation) in tissues and cells. Cell proliferation, migration, invasion, cycle and apoptosis were measured by CCK-8, transwell and flow cytometry assays, respectively. Ki67 level and lung metastasis were determined by immunochemistry and H&E staining. In this study, we found that CLEC5A was highly upregulated in glioblastoma compared to normal brain tissues, which had an opposite relation with the overall patient survival. Downregulation of CLEC5A could inhibit cell proliferation, migration and invasion via promoting apoptosis and G1 arrest. In contrast, overexpression of CLEC5A stimulated cell proliferation, migration and invasion. In addition, we found that CLEC5A level was positively correlated with Akt phosphorylation level. Akt inhibitor or agonist could reverse the modulation effects of CLEC5A in glioblastoma. Moreover, In vivo results suggested that inhibition of CLEC5A significantly reduced tumour size, weight, cell proliferation ability and lung metastasis via inhibition of phosphorylation Akt. Both in vitro and in vivo evidences supported that CLEC5A was involved in glioblastoma pathogenesis via regulation of PI3K/Akt pathway. Thus, CLEC5A might serve as a potential therapeutic target in the treatment of glioblastoma in the future.

Fan HW ，Ni Q ，Fan YN ，Ma ZX ，Li YB ... -  《-》

FOXD1-AS1 regulates FOXD1 translation and promotes gastric cancer progression and chemoresistance by activating the PI3K/AKT/mTOR pathway.

Gastric cancer (GC) is a common gastrointestinal cancer with a high global mortality. Recent reports have suggested that long noncoding RNA (lncRNA) are implicated in multiple aspects of GC, including pathogenesis, progression, and therapeutic response. Herein, we investigated the function of FOXD1-AS1 in GC progression and chemoresistance. Expression of FOXD1-AS1 was low in normal stomach tissues but was upregulated in GC cell lines. Silencing of FOXD1-AS1 impaired GC cell proliferation and motility in vitro, and repressed tumor growth and metastasis in vivo. Importantly, FOXD1-AS1 upregulation increased the resistance of GC cells to cisplatin. Moreover, we found that FOXD1-AS1 promoted FOXD1 protein translation through the eIF4G-eIF4E-eIF4A translational complex. We also demonstrated that FOXD1-AS1 released eIF4E from phosphorylated 4E-BP1 and thereby strengthened the interaction of eIF4E with eIF4G by activating the PI3K/AKT/mTOR pathway. Activation of the PI3K/AKT/mTOR pathway was due to the post-transcriptional upregulation of PIK3CA, in turn induced by FOXD1-AS1-mediated sequestering of microRNA (miR)-466. Furthermore, we verified that FOXD1-AS1 facilitated GC progression and cisplatin resistance in a FOXD1-dependent manner. In conclusion, FOXD1-AS1 aggravates GC progression and chemoresistance by promoting FOXD1 translation via PIK3CA/PI3K/AKT/mTOR signaling. These findings highlight a novel target for treatment of patients GC, particularly patients with cisplatin resistance.

Wu Q ，Ma J ，Wei J ，Meng W ，Wang Y ，Shi M ... -  《-》

CYP2E1 changes the biological function of gastric cancer cells via the PI3K/Akt/mTOR signaling pathway.

Wang RY ，Chen XW ，Zhang WW ，Jiang F ，Liu MQ ，Shen XB ... -  《-》

Long Non-Coding RNA XLOC_006753 Promotes the Development of Multidrug Resistance in Gastric Cancer Cells Through the PI3K/AKT/mTOR Signaling Pathway.

The development of multidrug resistance (MDR), which results in disease recurrence and metastasis, is a crucial obstacle to successful chemotherapy for patients with gastric cancer (GC). Long non-coding RNAs (lncRNAs) have been found to play various roles in cancer. This study aimed to investigate the effect of XLOC_006753 on the development of MDR in GC cells. The expression levels of XLOC_006753 in GC patients and MDR GC cell lines (SGC-7901/5-FU and SGC-7901/DDP cell line) were assessed by qRT-PCR. Statistical analyses were conducted to determine the relationship between XLOC_006753 expression and clinical features and to assess the prognostic value of XLOC_006753 for overall survival and progression-free survival. Then, a CCK-8 assay was used to detect cell proliferation ability and chemosensitivity. Flow cytometry was used to detect cell cycle and cell apoptosis. A wound-healing assay and transwell assay were used to detect cell migration. The expression of markers for MDR, G1/S transition, epithelial-mesenchymal transition (EMT) and PI3K/ AKT/mTOR signaling pathway were examined by western blot. XLOC_006753 was highly expressed in GC patients and MDR GC cell lines (SGC-7901/5-FU and SGC-7901/DDP cell lines), and its high expression was positively associated with metastasis, TNM stage, tumor size, and poor survival in GC patients. Moreover, XLOC_006753 was an independent prognostic biomarker of overall survival and progression-free survival for gastric cancer patients. Knocking down XLOC_006753 in the two MDR GC cell lines significantly inhibited cell proliferation, cell viability, cell cycle G1/S transition, and migration. XLOC_006753 knockdown also promoted apoptosis. Furthermore, western blots showed that XLOC_006753 knockdown decreased some markers of MDR, G1/S transition, and EMT expression, while increasing caspase9 expression and inhibiting the PI3K/AKT/mTOR signaling pathway in SGC-7901/5-FU and SGC-7901/DDP cells. High expression of XLOC_006753 promoted the development of MDR, which was activated by the PI3K/AKT/mTOR pathway in GC cells.

Zeng L ，Liao Q ，Zou Z ，Wen Y ，Wang J ，Liu C ，He Q ，Weng N ，Zeng J ，Tang H ，Fang R ，Lei Z ，Tang Z ，Yang X ，Cui S ... -  《-》