USP14 as a novel prognostic marker promotes cisplatin resistance via Akt/ERK signaling pathways in gastric cancer
Abstract 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 he...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2018-11-01
|
| Series: | Cancer Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cam4.1770 |
| _version_ | 1797681451102109696 |
|---|---|
| author | Ying Fu Gang Ma Guolong Liu Bin Li Hui Li Xishan Hao Liren Liu |
| author_facet | Ying Fu Gang Ma Guolong Liu Bin Li Hui Li Xishan Hao Liren Liu |
| author_sort | Ying Fu |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-11T23:45:01Z |
| format | Article |
| id | doaj.art-7a3777877760468bbb6abadd338986c4 |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2024-03-11T23:45:01Z |
| publishDate | 2018-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj.art-7a3777877760468bbb6abadd338986c42023-09-19T11:30:57ZengWileyCancer Medicine2045-76342018-11-017115577558810.1002/cam4.1770USP14 as a novel prognostic marker promotes cisplatin resistance via Akt/ERK signaling pathways in gastric cancerYing Fu0Gang Ma1Guolong Liu2Bin Li3Hui Li4Xishan Hao5Liren Liu6Department of Gastrointestinal Cancer Biology Tianjin Medical University Cancer Institute & Hospital National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy Tianjin; Tianjin’s Clinical Research Center for Cancer Tianjin 300060 ChinaDepartment of Gastrointestinal Cancer Biology Tianjin Medical University Cancer Institute & Hospital National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy Tianjin; Tianjin’s Clinical Research Center for Cancer Tianjin 300060 ChinaDepartment of Gastrointestinal Cancer Biology Tianjin Medical University Cancer Institute & Hospital National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy Tianjin; Tianjin’s Clinical Research Center for Cancer Tianjin 300060 ChinaDepartment of Gastrointestinal Surgery Tianjin Medical University Cancer Institute & Hospital National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy Tianjin; Tianjin’s Clinical Research Center for Cancer Tianjin 300060 ChinaDepartment of Gastrointestinal Cancer Biology Tianjin Medical University Cancer Institute & Hospital National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy Tianjin; Tianjin’s Clinical Research Center for Cancer Tianjin 300060 ChinaDepartment of Gastrointestinal Surgery Tianjin Medical University Cancer Institute & Hospital National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy Tianjin; Tianjin’s Clinical Research Center for Cancer Tianjin 300060 ChinaDepartment of Gastrointestinal Cancer Biology Tianjin Medical University Cancer Institute & Hospital National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy Tianjin; Tianjin’s Clinical Research Center for Cancer Tianjin 300060 ChinaAbstract 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.https://doi.org/10.1002/cam4.1770chemoresistancedeubiquitylasesgastric cancerUSP14 |
| spellingShingle | Ying Fu Gang Ma Guolong Liu Bin Li Hui Li Xishan Hao Liren Liu USP14 as a novel prognostic marker promotes cisplatin resistance via Akt/ERK signaling pathways in gastric cancer Cancer Medicine chemoresistance deubiquitylases gastric cancer USP14 |
| title | USP14 as a novel prognostic marker promotes cisplatin resistance via Akt/ERK signaling pathways in gastric cancer |
| title_full | USP14 as a novel prognostic marker promotes cisplatin resistance via Akt/ERK signaling pathways in gastric cancer |
| title_fullStr | USP14 as a novel prognostic marker promotes cisplatin resistance via Akt/ERK signaling pathways in gastric cancer |
| title_full_unstemmed | USP14 as a novel prognostic marker promotes cisplatin resistance via Akt/ERK signaling pathways in gastric cancer |
| title_short | USP14 as a novel prognostic marker promotes cisplatin resistance via Akt/ERK signaling pathways in gastric cancer |
| title_sort | usp14 as a novel prognostic marker promotes cisplatin resistance via akt erk signaling pathways in gastric cancer |
| topic | chemoresistance deubiquitylases gastric cancer USP14 |
| url | https://doi.org/10.1002/cam4.1770 |
| work_keys_str_mv | AT yingfu usp14asanovelprognosticmarkerpromotescisplatinresistanceviaakterksignalingpathwaysingastriccancer AT gangma usp14asanovelprognosticmarkerpromotescisplatinresistanceviaakterksignalingpathwaysingastriccancer AT guolongliu usp14asanovelprognosticmarkerpromotescisplatinresistanceviaakterksignalingpathwaysingastriccancer AT binli usp14asanovelprognosticmarkerpromotescisplatinresistanceviaakterksignalingpathwaysingastriccancer AT huili usp14asanovelprognosticmarkerpromotescisplatinresistanceviaakterksignalingpathwaysingastriccancer AT xishanhao usp14asanovelprognosticmarkerpromotescisplatinresistanceviaakterksignalingpathwaysingastriccancer AT lirenliu usp14asanovelprognosticmarkerpromotescisplatinresistanceviaakterksignalingpathwaysingastriccancer |