Flotillin-1 promotes progression and dampens chemosensitivity to cisplatin in gastric cancer via ERK and AKT signaling pathways.

Several past studies have reported the overexpression of Flotillin-1 in a variety of cancer types. Cisplatin is a chemotherapeutic drug commonly used for cancer treatment. The present study investigated the role of Flotillin-1 in the progression of GC and assessed whether it assists in the chemical sensitization of GC cells toward cisplatin. The expression of Flotillin-1 was detected both in human gastric mucosal cells and GC cells. Next, siRNA and shRNA were used to construct a stable cell line expressing low levels of Flotillin-1. Furthermore, the Cell Counting Kit 8 (CCK-8), flow cytometry, and transwell assays were employed to detect the impact of Flotillin-1 on GC cells. In addition, a nude mouse model of human GC was used to verify the knockdown of Flotillin-1 to increase the sensitivity of GC cells to cisplatin. Flotillin-1 was overexpressed in GC cells when compared to that in human gastric mucosal cells. The results for in vitro and vivo assays revealed that the knockdown of Flotillin-1 could significantly inhibit the proliferation of GC cells and increased the sensitivity of GC cells to cisplatin via the regulation of the protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) signaling pathway. Flotillin-1 might be used as a molecular marker for GC diagnosis and could be explored as a potential new target for the treatment of GC.

Wei J ，Wang R ，Lu Y ，He S ，Ding Y ... -  《-》

Psoriasin overexpression confers drug resistance to cisplatin by activating ERK in gastric cancer.

Li L ，Cui Y ，Ye L ，Zhao Z ，Jiang WG ，Ji J ... -  《-》

LncRNA SNHG6 knockdown inhibits cisplatin resistance and progression of gastric cancer through miR-1297/BCL-2 axis.

Cisplatin (DDP) resistance is a huge obstacle to gastric cancer (GC) treatment. Long non-coding RNAs (lncRNAs) have been manifested to exert pivotal functions in GC development. Herein, we aimed to explore the functional impact of lncRNA small nucleolar RNA host gene 6 (SNHG6) on DDP resistance and progression of GC. Quantitative real-time PCR (qRT-PCR) assay or Western blotting was performed to detect the expression of SNHG6, microRNA(miR)-1297, and epithelial-mesenchymal transition (EMT)-related factors and B-Cell Lymphoma 2 (Bcl-2) in DDP-resistant GC cells. Half inhibition concentration (IC50) to DDP, clonogenicity, apoptosis and invasion were examined via CCK-8 assay, colony formation assay, flow cytometry and Transwell assay, respectively. Target association between miR-1297 and SNHG6 or BCL-2 was demonstrated via dual-luciferase reporter assay or RIP assay. Xenograft models in nude mice were formed to investigate role of SNHG6 in vivo. We found that SNHG6 and BCL-2 were up-regulated, while miR-1297 expression was declined in GC tissues and DDP-resistant cells. Moreover, depletion of SNHG6 or gain of miR-1297 could repress DDP resistance, proliferation and metastasis of DDP-resistant cells, which was weakened by miR-1297 inhibition or BCL-2 overexpression. Besides, SNHG6 positively regulated BCL-2 expression by sponging miR-1297. Furthermore, SNHG6 knockdown repressed GC tumor growth in vivo. In a word, lncRNA SNHG6 knockdown had inhibitory effects on DDP resistance and progression of GC by sponging miR-1297, highlighting its potential in GC treatment.

Mei J ，Liu G ，Li R ，Xiao P ，Yang D ，Bai H ，Hao Y ... -  《-》

Knockdown of long non-coding RNA HOTAIR inhibits cisplatin resistance of gastric cancer cells through inhibiting the PI3K/Akt and Wnt/β-catenin signaling pathways by up-regulating miR-34a.

HOX transcript antisense RNA (HOTAIR), a well-known long non-coding RNA (lncRNA), has been reported to be related to cisplatin (DDP) resistance in gastric cancers. However, the molecular mechanism of HOTAIR in DDP resistance of gastric cancer (GC) remains largely undefined. The aim of this study was to investigate the role and underlying mechanism of HOTAIR in regulating cisplatin resistance of GC. The results showed that HOTAIR was over-expressed in GC tissues and GC cell lines, while miR-34a was low-expressed. Luciferase reporter assay and RIP assay proved that HOTAIR directly bound to miR-34a. MiR-34a expression was significantly increased in si-HOTAIR-transfected cells. Anti-miR-34a reversed the effect of si-HOTAIR on the DDP resistance, apoptosis-related genes, PI3K/Akt and Wnt/β-catenin signaling pathways in DDP-resistant GC cells, indicating that the effects of HOTAIR are dependent on miR-34a. In addition, knockdown of HOTAIR enhanced DDP inhibitory effect on tumor growth in vivo. In conclusion, HOTAIR knockdown inhibited DDP resistance of gastric cancer cells by upregulating miR-34a. The effect of HOTAIR/miR-34a axis on GC cells may be involved in the PI3K/Akt and Wnt/β-catenin signaling pathways. The results indicated that HOTAIR might be a new potential target in GC therapy.

Cheng C ，Qin Y ，Zhi Q ，Wang J ，Qin C ... -  《-》

USP14 as a novel prognostic marker promotes cisplatin resistance via Akt/ERK signaling pathways in gastric cancer.

Gastric cancer (GC) ranks the third leading cause of global cancer mortality. Despite recent progress in surgery combined with chemotherapy, the outcomes of GC patients have barely improved. Therefore, better understanding of the molecular mechanisms involved in chemoresistance of GC may help develop novel strategies to treat this deadly disease. Previous evidence has shown aberrant expressions of USP14 in multiple malignancies, suggesting an important role of USP14 in tumorigenesis. However, its role in modulating chemoresistance in GC still remains elusive. In this study, we observed that USP14 levels were significantly increased in GC tissues compared to the paired normal tissues. Multivariate analysis demonstrated that USP14 level was an independent prognostic factor for DFS in GC patients. Silencing of USP14 promoted proteasomal degradation of p-ERK (T202/Y204) and p-Akt (T308/S473), thus inactivating Akt and ERK signaling pathways. Interestingly, silencing of USP14 alone was not sufficient to cause overt effects on cell growth, proliferation, and apoptosis, while resulting in significant apoptosis in the presence of cisplatin in GC cells. Thus, knockdown of USP14 sensitized GC cells to cisplatin by triggering cisplatin-induced apoptosis via impeding Akt and ERK signaling pathways. These results revealed a novel role of USP14 in modulating chemosensitivity of GC cells, suggesting USP14 may serve as not only a prognostic marker, but also a potential therapeutic target for GC patients.

Fu Y ，Ma G ，Liu G ，Li B ，Li H ，Hao X ，Liu L ... -  《Cancer Medicine》