Abstract
BackgroundGastric cancer (GC) is the second leading cause of cancer-related deaths. Because it is hard to diagnose at early stage, the overall 5 years survival rate is lower than 25%. High migration is the main hallmark of malignant cells at advanced stage of GC. Thus, it is urgent to find biomarkers for early diagnosis and more effective therapy of GC.MethodsIn this study, lentivirus-mediated silencing and overexpression lentiviruses targeting the ubiquitin-conjugating enzyme E2 D1 (UBE2D1), transwell, wound healing, and pulmonary metastasis mouse model were applied to analyze the function of UBE2D1 in vitro and in vivo. Real-time PCR and immunohistochemistry were used to elucidate the level of UBE2D1 in GC samples.ResultsSilencing of UBE2D1 inhibited cell migration and the levels of epithelial-mesenchymal transition makers (MMP2 and MMP9) in AGS and MKN45 cells. Silencing of UBE2D1 inhibited cell metastasis in mouse model. On the contrary, UBE2D1 overexpression increased cell migration and the levels of MMP2 and MMP9 in MGC-803 cells. Further, silencing of UBE2D1 decreased the ubiquitination level of mothers against decapentaplegic homolog 4 (SMAD4), and the increase of cell migration induced by UBE2D1 overexpression could be reversed by SMAD4.ConclusionSilencing of UBE2D1 inhibited cell migration through transforming growth factor β (TGF-β)/SMAD4 signaling pathway in GC.
Highlights
Gastric cancer (GC) is the second leading cause of cancer-related deaths
ubiquitin-conjugating enzyme E2 D1 (UBE2D1) is elevated in GC tissues and correlated with poor prognosis To determine the significance of UBE2D1 in GC, we analyzed the expression level of UBE2D1 in TCGA-STAD and found that UBE2D1 was upregulated in primary tumor (n = 415) compared to the normal tissue (n = 14, Fig. 1A)
According to the results of IHC staining with GC tissue array (Fig. 1C), GC tumors (68.75%) expressed much higher protein level of UBE2D1 than the paracancerous tissues
Summary
Because it is hard to diagnose at early stage, the overall 5 years survival rate is lower than 25%. High migration is the main hallmark of malignant cells at advanced stage of GC. Gastric cancer (GC), a common malignant tumor of the digestive system, is the second leading cause of cancerrelated deaths, with an overall 5 years survival rate lower than 25% [1]. Transforming growth factor β (TGF-β) signaling pathway is of great importance in regulating a large number of biological processes, including cell proliferation, apoptosis, differentiation, migration, and the initiation and progression of cancer [5]. Mothers against decapentaplegic homolog 4 (SMAD4), the central mediator of TGF-β signaling, plays a vital role in signal transferring from cell membrane to nucleus [6]. The canonical TGF-β/ SMAD4 signaling pathway has been demonstrated to be
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