MTMR2 promotes invasion and metastasis of gastric cancer via inactivating IFNγ/STAT1 signaling
Abstract Background The aberrant expression of myotubularin-related protein 2 (MTMR2) has been found in some cancers, but little is known about the roles and clinical relevance. The present study aimed to investigate the roles and clinical relevance of MTMR2 as well as the underlying mechanisms in g...
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| Format: | Article |
| Language: | English |
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BMC
2019-05-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-019-1186-z |
| _version_ | 1818239796010549248 |
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| author | Lei Jiang Jun-yan Liu Yan Shi Bo Tang Tao He Jia-jia Liu Jun-yan Fan Bin Wu Xian-hui Xu Yong-liang Zhao Feng Qian You-hong Cui Pei-wu Yu |
| author_facet | Lei Jiang Jun-yan Liu Yan Shi Bo Tang Tao He Jia-jia Liu Jun-yan Fan Bin Wu Xian-hui Xu Yong-liang Zhao Feng Qian You-hong Cui Pei-wu Yu |
| author_sort | Lei Jiang |
| collection | DOAJ |
| description | Abstract Background The aberrant expression of myotubularin-related protein 2 (MTMR2) has been found in some cancers, but little is known about the roles and clinical relevance. The present study aimed to investigate the roles and clinical relevance of MTMR2 as well as the underlying mechanisms in gastric cancer (GC). Methods MTMR2 expression was examined in 295 GC samples by using immunohistochemistry (IHC). The correlation between MTMR2 expression and clinicopathological features and outcomes of the patients was analyzed. The roles of MTMR2 in regulating the invasive and metastatic capabilities of GC cells were observed using gain-and loss-of-function assays both in vitro and in vivo. The pathways involved in MTMR2-regulating invasion and metastasis were selected and identified by using mRNA expression profiling. Functions and underlying mechanisms of MTMR2-mediated invasion and metastasis were further investigated in a series of in vitro studies. Results MTMR2 was highly expressed in human GC tissues compared to adjacent normal tissues and its expression levels were significantly correlated with depth of invasion, lymph node metastasis, and TNM stage. Patients with MTMR2high had significantly shorter lifespan than those with MTMR2low. Cox regression analysis showed that MTMR2 was an independent prognostic indicator for GC patients. Knockdown of MTMR2 significantly reduced migratory and invasive capabilities in vitro and metastases in vivo in GC cells, while overexpressing MTMR2 achieved the opposite results. MTMR2 knockdown and overexpression markedly inhibited and promoted the epithelial-mesenchymal transition (EMT), respectively. MTMR2 mediated EMT through the IFNγ/STAT1/IRF1 pathway to promote GC invasion and metastasis. Phosphorylation of STAT1 and IRF1 was increased by MTMR2 knockdown and decreased by MTMR2 overexpression accompanying with ZEB1 down-regulation and up-regulation, respectively. Silencing IRF1 upregulated ZEB1, which induced EMT and consequently enhanced invasion and metastasis in GC cells. Conclusions Our findings suggest that MTMR2 is an important promoter in GC invasion and metastasis by inactivating IFNγ/STAT1 signaling and may act as a new prognostic indicator and a potential therapeutic target for GC. |
| first_indexed | 2024-12-12T13:03:14Z |
| format | Article |
| id | doaj.art-84fe894a5c5f4093a9fa854be371ce40 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-12T13:03:14Z |
| publishDate | 2019-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-84fe894a5c5f4093a9fa854be371ce402022-12-22T00:23:44ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662019-05-0138111610.1186/s13046-019-1186-zMTMR2 promotes invasion and metastasis of gastric cancer via inactivating IFNγ/STAT1 signalingLei Jiang0Jun-yan Liu1Yan Shi2Bo Tang3Tao He4Jia-jia Liu5Jun-yan Fan6Bin Wu7Xian-hui Xu8Yong-liang Zhao9Feng Qian10You-hong Cui11Pei-wu Yu12Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University (Army Medical University)Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University (Army Medical University)Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University (Army Medical University)Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University (Army Medical University)Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University (Army Medical University)Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University (Army Medical University)Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University (Army Medical University)Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University (Army Medical University)Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University (Army Medical University)Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University (Army Medical University)Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University (Army Medical University)Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University (Army Medical University)Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University (Army Medical University)Abstract Background The aberrant expression of myotubularin-related protein 2 (MTMR2) has been found in some cancers, but little is known about the roles and clinical relevance. The present study aimed to investigate the roles and clinical relevance of MTMR2 as well as the underlying mechanisms in gastric cancer (GC). Methods MTMR2 expression was examined in 295 GC samples by using immunohistochemistry (IHC). The correlation between MTMR2 expression and clinicopathological features and outcomes of the patients was analyzed. The roles of MTMR2 in regulating the invasive and metastatic capabilities of GC cells were observed using gain-and loss-of-function assays both in vitro and in vivo. The pathways involved in MTMR2-regulating invasion and metastasis were selected and identified by using mRNA expression profiling. Functions and underlying mechanisms of MTMR2-mediated invasion and metastasis were further investigated in a series of in vitro studies. Results MTMR2 was highly expressed in human GC tissues compared to adjacent normal tissues and its expression levels were significantly correlated with depth of invasion, lymph node metastasis, and TNM stage. Patients with MTMR2high had significantly shorter lifespan than those with MTMR2low. Cox regression analysis showed that MTMR2 was an independent prognostic indicator for GC patients. Knockdown of MTMR2 significantly reduced migratory and invasive capabilities in vitro and metastases in vivo in GC cells, while overexpressing MTMR2 achieved the opposite results. MTMR2 knockdown and overexpression markedly inhibited and promoted the epithelial-mesenchymal transition (EMT), respectively. MTMR2 mediated EMT through the IFNγ/STAT1/IRF1 pathway to promote GC invasion and metastasis. Phosphorylation of STAT1 and IRF1 was increased by MTMR2 knockdown and decreased by MTMR2 overexpression accompanying with ZEB1 down-regulation and up-regulation, respectively. Silencing IRF1 upregulated ZEB1, which induced EMT and consequently enhanced invasion and metastasis in GC cells. Conclusions Our findings suggest that MTMR2 is an important promoter in GC invasion and metastasis by inactivating IFNγ/STAT1 signaling and may act as a new prognostic indicator and a potential therapeutic target for GC.http://link.springer.com/article/10.1186/s13046-019-1186-zMyotubularin-related protein 2Gastric cancerInvasionEpithelial- mesenchymal transition (EMT)IFNγ/STAT1 signaling |
| spellingShingle | Lei Jiang Jun-yan Liu Yan Shi Bo Tang Tao He Jia-jia Liu Jun-yan Fan Bin Wu Xian-hui Xu Yong-liang Zhao Feng Qian You-hong Cui Pei-wu Yu MTMR2 promotes invasion and metastasis of gastric cancer via inactivating IFNγ/STAT1 signaling Journal of Experimental & Clinical Cancer Research Myotubularin-related protein 2 Gastric cancer Invasion Epithelial- mesenchymal transition (EMT) IFNγ/STAT1 signaling |
| title | MTMR2 promotes invasion and metastasis of gastric cancer via inactivating IFNγ/STAT1 signaling |
| title_full | MTMR2 promotes invasion and metastasis of gastric cancer via inactivating IFNγ/STAT1 signaling |
| title_fullStr | MTMR2 promotes invasion and metastasis of gastric cancer via inactivating IFNγ/STAT1 signaling |
| title_full_unstemmed | MTMR2 promotes invasion and metastasis of gastric cancer via inactivating IFNγ/STAT1 signaling |
| title_short | MTMR2 promotes invasion and metastasis of gastric cancer via inactivating IFNγ/STAT1 signaling |
| title_sort | mtmr2 promotes invasion and metastasis of gastric cancer via inactivating ifnγ stat1 signaling |
| topic | Myotubularin-related protein 2 Gastric cancer Invasion Epithelial- mesenchymal transition (EMT) IFNγ/STAT1 signaling |
| url | http://link.springer.com/article/10.1186/s13046-019-1186-z |
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