Open AccessUSP 14 as a novel prognostic marker promotes cisplatin resistance via Akt/ ERK signaling pathways in gastric cancer
Author(s) -
Fu Ying,
Ma Gang,
Liu Guolong,
Li Bin,
Li Hui,
Hao Xishan,
Liu Liren
Publication year - 2018
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.1770
Subject(s) - protein kinase b , cisplatin , gene silencing , mapk/erk pathway , apoptosis , cancer research , cancer , carcinogenesis , signal transduction , medicine , gene knockdown , chemistry , biology , chemotherapy , microbiology and biotechnology , biochemistry , gene
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 USP 14 in multiple malignancies, suggesting an important role of USP 14 in tumorigenesis. However, its role in modulating chemoresistance in GC still remains elusive. In this study, we observed that USP 14 levels were significantly increased in GC tissues compared to the paired normal tissues. Multivariate analysis demonstrated that USP 14 level was an independent prognostic factor for DFS in GC patients. Silencing of USP 14 promoted proteasomal degradation of p‐ ERK (T202/Y204) and p‐Akt (T308/S473), thus inactivating Akt and ERK signaling pathways. Interestingly, silencing of USP 14 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 USP 14 sensitized GC cells to cisplatin by triggering cisplatin‐induced apoptosis via impeding Akt and ERK signaling pathways. These results revealed a novel role of USP 14 in modulating chemosensitivity of GC cells, suggesting USP 14 may serve as not only a prognostic marker, but also a potential therapeutic target for GC patients.