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》

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 ... -  《-》

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 ... -  《-》

SDC2 Stabilization by USP14 Promotes Gastric Cancer Progression through Co-option of PDK1.

Gastric cancer (GC) is a common malignancy and remains the fourth-leading cause of cancer-related deaths worldwide. Oncogenic potential of SDC2 has been implicated in multiple types of cancers, yet its role and underlying molecular mechanisms in GC remain unknown. Here, we found that SDC2 was highly expressed in GC and its upregulation correlated with poor prognosis in GC patients. Depletion of SDC2 significantly suppressed the growth and invasive capability of GC cells, while overexpressing SDC2 exerts opposite effects. Combined bioinformatics and experimental analyses substantiated that overexpression of SDC2 activated the AKT signaling pathway in GC, mechanistically through the interaction between SDC2 and PDK1-PH domain, thereby facilitating PDK1 membrane translocation to promote AKT activation. Moreover, SDC2 could also function as a co-receptor for FGF2 and was profoundly involved in the FGF2-AKT signaling axis in GC. Lastly, we revealed a mechanism on the USP14-mediated stabilization of SDC2 that is likely to contribute to SDC2 upregulation in GC tissues. Furthermore, we showed that IU1, a potent USP14 inhibitor, decreased the abundance of SDC2 in GC cells. Our findings indicate that SDC2 functions as a novel GC oncogene and has potential utility as a diagnostic marker and therapeutic target for GC.

You L ，Dou Y ，Zhang Y ，Xiao H ，Lv H ，Wei GH ，Xu D ... -  《International Journal of Biological Sciences》

Inhibition of ubiquitin‑specific protease 14 promotes connexin 32 internalization and counteracts cisplatin cytotoxicity in human ovarian cancer cells.

Luo H ，Wang X ，Ge H ，Zheng N ，Peng F ，Fu Y ，Tao L ，Wang Q ... -  《-》