Abstract
BackgroundThe 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).MethodsMTMR2 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.ResultsMTMR2 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.ConclusionsOur 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.
Highlights
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
We demonstrated that more effective treatments.Myotubularin-related protein 2 (MTMR2) highly expressed in gastric cancer (GC) tissues and its expression levels were significantly correlated with invasion depth and lymph node metastasis, as well as the outcome of the patients
In summary, we demonstrate that MTMR2 promotes epithelial-mesenchymal transition (EMT), invasion and metastasis by inactivating the IFNγ/ Janus activated kinase (JAK)/STAT1/IRF1 signaling, a canonical pathway for IFNγ, to provoke ZEB1 expression in GC cells
Summary
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). Gastric cancer (GC) remains the fifth most common cancer type and the third leading cause of cancer-related deaths worldwide [1]. MTMR2 mutation causes Charcot-Marie-Tooth type 4B1 (CMT4B1), a recessive demyelinating neuropathy characterized by myelin sheaths folded and severe axonal loss [8]. In patients with Sézary syndrome, an aggressive, leukemic cutaneous T-cell lymphoma variant, MTMR2 was involved in rearrangements affecting gene expression [11]. The roles, mechanisms and clinical relevance of MTMR2 in GC have not been investigated
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