Regulation of Integrin Subunit Alpha 2 by miR-135b-5p Modulates Chemoresistance in Gastric Cancer
Chemotherapy has substantially improved gastric cancer (GC) patient outcomes in the past decades. However, the development of chemotherapy resistance has become the major cause of treatment failure. Although numerous molecules have been implicated in GC chemoresistance, its pathological mechanisms a...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-03-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2020.00308/full |
| _version_ | 1818486595497492480 |
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| author | Qi Wang Tianyu Cao Kai Guo Yao Zhou Hao Liu Yanan Pan Qiuqiu Hou Yongzhan Nie Daiming Fan Yuanyuan Lu Xiaodi Zhao Xiaodi Zhao |
| author_facet | Qi Wang Tianyu Cao Kai Guo Yao Zhou Hao Liu Yanan Pan Qiuqiu Hou Yongzhan Nie Daiming Fan Yuanyuan Lu Xiaodi Zhao Xiaodi Zhao |
| author_sort | Qi Wang |
| collection | DOAJ |
| description | Chemotherapy has substantially improved gastric cancer (GC) patient outcomes in the past decades. However, the development of chemotherapy resistance has become the major cause of treatment failure. Although numerous molecules have been implicated in GC chemoresistance, its pathological mechanisms are still unclear. Here, we found that integrin subunit alpha 2 (ITGA2) is upregulated in chemoresistant GC cells and that increased ITGA2 levels correlated with the poor prognosis of GC patients who received chemotherapy. ITGA2 overexpression led to elevated chemotherapy resistance and drug-induced apoptosis inhibition in GC cells. ITGA2 knockdown resulted in restored chemosensitivity and increased apoptosis in chemoresistant GC cells both in vitro and in vivo. NanoString analysis revealed a unique signature of deregulated pathway expression in GC cells after ITGA2 silencing. The MAPK/ERK pathway and epithelial-mesenchymal transition (EMT) were found to be downregulated after ITGA2 knockdown. miR-135b-5p was identified as a direct upstream regulator of ITGA2. miR-135b-5p overexpression reduced chemoresistance and induced apoptosis in GC cells and attenuated ITGA2-induced chemoresistance and antiapoptotic effects by inhibiting MAPK signaling and EMT. In conclusion, this study underscored the role and mechanism of ITGA2 in GC and suggested the novel miR-135b-5p/ITGA2 axis as an epigenetic cause of chemoresistance with diagnostic and therapeutic implications. |
| first_indexed | 2024-12-10T16:25:06Z |
| format | Article |
| id | doaj.art-a4ba5ad71e8e4289890cf1ae4f86caf4 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-10T16:25:06Z |
| publishDate | 2020-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-a4ba5ad71e8e4289890cf1ae4f86caf42022-12-22T01:41:42ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2020-03-011010.3389/fonc.2020.00308510398Regulation of Integrin Subunit Alpha 2 by miR-135b-5p Modulates Chemoresistance in Gastric CancerQi Wang0Tianyu Cao1Kai Guo2Yao Zhou3Hao Liu4Yanan Pan5Qiuqiu Hou6Yongzhan Nie7Daiming Fan8Yuanyuan Lu9Xiaodi Zhao10Xiaodi Zhao11State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaState Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaDepartment of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaGuangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, ChinaState Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaCollege of Life Sciences, Northwest University, Xi'an, ChinaCollege of Life Sciences, Northwest University, Xi'an, ChinaState Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaState Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaState Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaState Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, ChinaNational Institute of Biological Sciences, Beijing, ChinaChemotherapy has substantially improved gastric cancer (GC) patient outcomes in the past decades. However, the development of chemotherapy resistance has become the major cause of treatment failure. Although numerous molecules have been implicated in GC chemoresistance, its pathological mechanisms are still unclear. Here, we found that integrin subunit alpha 2 (ITGA2) is upregulated in chemoresistant GC cells and that increased ITGA2 levels correlated with the poor prognosis of GC patients who received chemotherapy. ITGA2 overexpression led to elevated chemotherapy resistance and drug-induced apoptosis inhibition in GC cells. ITGA2 knockdown resulted in restored chemosensitivity and increased apoptosis in chemoresistant GC cells both in vitro and in vivo. NanoString analysis revealed a unique signature of deregulated pathway expression in GC cells after ITGA2 silencing. The MAPK/ERK pathway and epithelial-mesenchymal transition (EMT) were found to be downregulated after ITGA2 knockdown. miR-135b-5p was identified as a direct upstream regulator of ITGA2. miR-135b-5p overexpression reduced chemoresistance and induced apoptosis in GC cells and attenuated ITGA2-induced chemoresistance and antiapoptotic effects by inhibiting MAPK signaling and EMT. In conclusion, this study underscored the role and mechanism of ITGA2 in GC and suggested the novel miR-135b-5p/ITGA2 axis as an epigenetic cause of chemoresistance with diagnostic and therapeutic implications.https://www.frontiersin.org/article/10.3389/fonc.2020.00308/fullITGA2miR-135b-5pgastric cancerchemoresistanceMAPK pathwayEMT |
| spellingShingle | Qi Wang Tianyu Cao Kai Guo Yao Zhou Hao Liu Yanan Pan Qiuqiu Hou Yongzhan Nie Daiming Fan Yuanyuan Lu Xiaodi Zhao Xiaodi Zhao Regulation of Integrin Subunit Alpha 2 by miR-135b-5p Modulates Chemoresistance in Gastric Cancer Frontiers in Oncology ITGA2 miR-135b-5p gastric cancer chemoresistance MAPK pathway EMT |
| title | Regulation of Integrin Subunit Alpha 2 by miR-135b-5p Modulates Chemoresistance in Gastric Cancer |
| title_full | Regulation of Integrin Subunit Alpha 2 by miR-135b-5p Modulates Chemoresistance in Gastric Cancer |
| title_fullStr | Regulation of Integrin Subunit Alpha 2 by miR-135b-5p Modulates Chemoresistance in Gastric Cancer |
| title_full_unstemmed | Regulation of Integrin Subunit Alpha 2 by miR-135b-5p Modulates Chemoresistance in Gastric Cancer |
| title_short | Regulation of Integrin Subunit Alpha 2 by miR-135b-5p Modulates Chemoresistance in Gastric Cancer |
| title_sort | regulation of integrin subunit alpha 2 by mir 135b 5p modulates chemoresistance in gastric cancer |
| topic | ITGA2 miR-135b-5p gastric cancer chemoresistance MAPK pathway EMT |
| url | https://www.frontiersin.org/article/10.3389/fonc.2020.00308/full |
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