The significance of ENAH in carcinogenesis and prognosis in gastric cancer

Wang, Dandan; Jin, Qun; Wang, Leilei; Han, Shu-Fang; Chen, Yi-Bing; Sun, Guan; Sun, Shifei; Sun, Shu-Wang; Wang, Tao; Liu, Fan-jie; Wang, Ping; Shi, Bin

doi:10.18632/oncotarget.19801

Cited by 17 publications

(23 citation statements)

References 22 publications

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“…6. Similar to previous findings [16], high Mena expression was significantly associated with high rate of lymph node metastasis ( P = 0.024, Table 1) and worse prognosis ( P = 0.017, Fig. 7a).…”

Section: Resultssupporting

confidence: 90%

TES functions as a Mena‐dependent tumor suppressor in gastric cancer carcinogenesis and metastasis

Wang

Chen

Zhao

et al. 2019

Cancer Communications

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BackgroundIn our previous study, we identified a candidate tumor suppressor gene, testin LIM domain protein (TES), in primary gastric cancer (GC). TES contains three LIM domains, which are specific interacting regions for the cell adhesion and cytoskeleton regulatory proteins. Mena is a known cytoskeleton regulator that regulates the assembly of actin filaments and modulates cell adhesion and motility by interacting with Lamellipodin (Lpd). Therefore, we hypothesized that TES plays a role as tumor suppressor in GC through interacting with Mena. This study aimed to investigate the tumor suppressive functions of TES in GC.MethodsWe explored the tumor suppressive effect of TES in GC by in vitro cell proliferation assay, colony formation assay, cell cycle analysis, Transwell assays, and in vivo tumorigenicity and metastasis assays. The interaction of TES and Mena was investigated through immunoprecipitation-based mass spectrometry. We also analyzed the expression of TES and Mena in 172 GC specimens using immunohistochemistry and investigated the clinicopathological and prognostic significance of TES and Mena in GC.ResultsTES suppressed GC cell proliferation and colony formation, induced cell cycle arrest, and inhibited tumorigenicity in vitro. Additionally, it inhibited GC cell migration and invasion in vitro and suppressed metastasis in vivo. TES interacted with Mena, and inhibited the interaction of Mena with Lpd. Transwell assays suggested that TES suppressed migration and invasion of GC cells in a Mena-dependent fashion. In GC patients with high Mena expression, the expression of TES was associated with tumor infiltration (P = 0.005), lymph node metastasis (P = 0.003), TNM stage (P = 0.003), and prognosis (P = 0.010). However, no significant association was observed in GC patients with low Mena expression.ConclusionsWe believe that TES functions as a Mena-dependent tumor suppressor. TES represents a valuable prognostic marker and potential target for GC treatment.Electronic supplementary materialThe online version of this article (10.1186/s40880-019-0347-y) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 90%

TES functions as a Mena‐dependent tumor suppressor in gastric cancer carcinogenesis and metastasis

Wang

Chen

Zhao

et al. 2019

Cancer Communications

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“…Cell viability was assessed using a Promega Cell Titer 96 Aqueous One Solution (G3580, Madison, WI, USA) as previously described [26]. Briefly, cells were seeded in 96-well plates (500 per well) in 100 μl DEME medium for five replicates.…”

Section: Methodsmentioning

confidence: 99%

“…Colonies that contained > 50 stained cells were classed as clones. Colony-forming efficiency was calculated as a ratio of the number of colonies formed to the number of cells seeded and calibrated to that of untreated cells as previously described [26].…”

Section: Methodsmentioning

confidence: 99%

Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells

Chen

Zhang

et al. 2019

J Exp Clin Cancer Res

211

138

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Background Dihydroartemisinin (DHA) has been shown to exert anticancer activity through iron-dependent reactive oxygen species (ROS) generation, which is similar to ferroptosis, a novel form of cell death. However, whether DHA causes ferroptosis in glioma cells and the potential regulatory mechanisms remain unclear. Methods Effects of DHA on the proliferation, cell death, ROS and lipid ROS generation as well as reduced gluthione consumption were assessed in glioma cells with or without ferroptosis inhibitor. The biological mechanisms by which glioma cells attenuate the pro-ferroptotic effects of DHA were assessed using molecular methods. Results DHA induced ferroptosis in glioma cells, as characterized by iron-dependent cell death accompanied with ROS generation and lipid peroxidation. However, DHA treatment simultaneously activated a feedback pathway of ferroptosis by increasing the expression of heat shock protein family A (Hsp70) member 5 (HSPA5). Mechanistically, DHA caused endoplasmic reticulum (ER) stress in glioma cells, which resulted in the induction of HSPA5 expression by protein kinase R-like ER kinase (PERK)-upregulated activating transcription factor 4 (ATF4). Subsequent HSPA5 upregulation increased the expression and activity of glutathione peroxidase 4 (GPX4), which neutralized DHA-induced lipid peroxidation and thus protected glioma cells from ferroptosis. Inhibition of the PERK-ATF4-HSPA5-GPX4 pathway using siRNA or small molecules increased DHA sensitivity of glioma cells by increasing ferroptosis both in vitro and in vivo. Conclusions Collectively, these data suggested that ferroptosis might be a novel anticancer mechanism of DHA in glioma and HSPA5 may serve as a negative regulator of DHA-induced ferroptosis. Therefore, inhibiting the negative feedback pathway would be a promising therapeutic strategy to strengthen the anti-glioma activity of DHA.

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“…Commonly referred to as Mena, ENAH is a member of the Ena/vasodilator-stimulated phosphoprotein group and consists of actin-related proteins that play different roles in various cells [ 18 ]. Additionally, ENAH is highly expressed in gastric cancer and apparently enables its development, highlighting its potential as a prognostic marker for gastric cancer patients [ 19 ]. Based on the aforementioned exploration of literature, we hypothesized that exosomal miR-375 contributes to the development of ESCC by regulating ENAH expression.…”

Section: Introductionmentioning

confidence: 99%

Human umbilical cord mesenchymal stem cells-derived exosomes deliver microRNA-375 to downregulate ENAH and thus retard esophageal squamous cell carcinoma progression

Zheng

et al. 2020

J Exp Clin Cancer Res

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Background: Exosomal microRNAs (miRNAs or miRs) from bone marrow-derived mesenchymal stem cells (UCMSCs) have emerged as promising therapeutic strategies for cancer treatment. The current study aimed to elucidate the underlying mechanism of human umbilical cord mesenchymal stem cells (hUCMSCs)-derived exosomal miR-375 in esophageal squamous cell carcinoma (ESCC). Methods: After determining the expression of miR-375 and its putative target enabled homolog (ENAH) in ESCC tissues and cells, we tested effects of their altered expression on ESCC proliferation, invasion, migration, and tumorsphere formation was subsequently measured. Transfected hUCMSCs-derived exosomes (hUCMSCs-exo) were isolated and co-cultured with ESCC cells to measure the effects of miR-375 delivered by hUCMSCs-exo on ESCC development. Finally, we investigated the effect of miR-375 on tumor growth in vivo. Results: The expression of miR-375 was reduced, while the expression of ENAH was elevated in ESCC. ENAH was identified as a target gene of miR-375. Elevated miR-375 or depleted ENAH expression inhibited ESCC cell proliferation, invasion, migration, tumorsphere formation, and promoted apoptosis. Moreover, miR-375 delivered by hUCMSCs-exo could suppress ESCC cell proliferation, invasion, migration, tumorsphere formation, but promoted apoptosis in vitro, as well as inhibiting tumor growth in vivo. Conclusions: Taken together, hUCMSCs-exo can deliver miR-375 to suppress ENAH expression and subsequently inhibit the initiation and progression of ESCC.

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The significance of ENAH in carcinogenesis and prognosis in gastric cancer

Cited by 17 publications

References 22 publications

TES functions as a Mena‐dependent tumor suppressor in gastric cancer carcinogenesis and metastasis

TES functions as a Mena‐dependent tumor suppressor in gastric cancer carcinogenesis and metastasis

Dihydroartemisinin-induced unfolded protein response feedback attenuates ferroptosis via PERK/ATF4/HSPA5 pathway in glioma cells

Human umbilical cord mesenchymal stem cells-derived exosomes deliver microRNA-375 to downregulate ENAH and thus retard esophageal squamous cell carcinoma progression

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