MTMR2 promotes invasion and metastasis of gastric cancer via inactivating IFNγ/STAT1 signaling
Authors: Jun-Yan Liu
Feng Qian
Lei Jiang
Bo Tang
You-Hong Cui
Pei-Wu Yu
Jia-Jia Liu
Tao He
Yan Shi
Jun-Yan Fan
Yong-Liang Zhao
Bin Wu
Xian-Hui Xu
Journal: Journal of Experimental & Clinical Cancer Research (2019)
Discipline: CLINICAL MEDICINE
Keywords: Epithelial- mesenchymal transition (EMT); Gastric cancer; IFNγ/STAT1 signaling; Invasion; Myotubularin-related protein 2.
Affiliations: Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), No. 30 Gaotanyan Street, Chongqing, 400038, China., Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), No. 30 Gaotanyan Street, Chongqing, 400038, China. ., Institute of Pathology and Southwest Cancer Center, and Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Third Military Medical University (Army Medical University), No. 30 Gaotanyan Street, Chongqing, 400038, China. .

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. 

Retracted: No

PubPeer comments:
 Two images in Figure 6G appear to overlap. *** ![file] , 
 #1 Thank you very much for your reminder. Representative images of IHC staining of IRF1 in Fig 6G were placed by unintentional mistake during figure preparation. This correction does not change the conclusions of our paper. We are very sorry for our carelessness and sincerely apologize for this mistake. We will contact the journal for correction as soon as possible if necessary. ,