eIF6 promotes the malignant progression of human hepatocellular carcinoma via the mTOR signaling pathway

Sun, Liping; Liu, Shuguang; Wang, Xiaopai; Zheng, Xuefeng; Chen, Ya; Shen, Hong

doi:10.1186/s12967-021-02877-4

Cited by 18 publications

(13 citation statements)

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“…4EBP1 and p70S6K axes play critical and distinct roles in hepatocarcinogenesis 36 . The target genes of the mTOR pathway, such as MYC, Cyclin D1, HIF1α, and SREBP1, participate in many malignant behaviors of HCC cells 37 - 39 . Recent studies report that glutamine synthetase (GS), a transcriptional target of β-catenin, functions as a driver in HCC development by promoting p-mTOR (S2448) expression 40 - 42 .…”

Section: Discussionmentioning

confidence: 99%

UBE2O promotes hepatocellular carcinoma cell proliferation and invasion by regulating the AMPKα2/mTOR pathway

Shi¹,

Liu²,

Lu³

et al. 2021

Int. J. Med. Sci.

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The ubiquitin-conjugating enzyme (E2) is a critical component of the ubiquitin-proteasome system and regulates hepatocarcinogenesis by controlling protein degradation. Ubiquitin-conjugating enzyme E2 O (UBE2O), a member of the E2 family, functions as an oncogene in human cancers. Nevertheless, the role of UBE2O in hepatocellular carcinoma (HCC) remains unknown yet. Here, we demonstrated that the UBE2O level was markedly upregulated in HCC compared with adjacent noncancerous tissues. UBE2O overexpression was also confirmed in HCC cell lines. UBE2O overexpression was prominently associated with advanced tumor stage, high tumor grade, venous infiltration, and reduced HCC patients' survivals. UBE2O knockdown inhibited the migration, invasion, and proliferation of HCCLM3 cells. UBE2O overexpression enhanced the proliferation and mobility of Huh7 cells. Mechanistically, UBE2O mediated the ubiquitination and degradation of AMP-activated protein kinase α2 (AMPKα2) in HCC cells. UBE2O silencing prominently increased AMPKα2 level and reduced phosphorylated mechanistic target of rapamycin kinase (p-mTOR), MYC, Cyclin D1, HIF1α, and SREBP1 levels in HCCLM3 cells. UBE2O depletion markedly activated the AMPKα2/mTOR pathway in Huh7 cells. Moreover, AMPKα2 silencing reversed UBE2O downregulation-induced mTOR pathway inactivation. Rapamycin, an inhibitor of mTOR, remarkably abolished UBE2O-induced mTOR phosphorylation and HCC cell proliferation and mobility. To conclude, UBE2O was highly expressed in HCC and its overexpression conferred to the poor clinical outcomes of patients. UBE2O contributed to the malignant behaviors of HCC cells, including cell proliferation, migration, and invasion, by reducing AMPKα2 stability and activating the mTOR pathway.

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Section: Discussionmentioning

confidence: 99%

UBE2O promotes hepatocellular carcinoma cell proliferation and invasion by regulating the AMPKα2/mTOR pathway

Shi¹,

Liu²,

Lu³

et al. 2021

Int. J. Med. Sci.

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“…Therefore, it is reasonable to conclude that eIF6 is a critical regulator of tumor growth. Additionally, this hypothesis has also been proven because eIF6 knock-down could efficiently inhibit the progression of hepatocellular carcinoma and non-small cell lung carcinoma ( 21 , 24 ). Since it has been reported that eIF6 is essential for immune system homeostasis in both mice and humans, we also investigated the tumor immunology of eIF6.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, the skin melanoma samples exhibited significantly increased eIF6 expression levels than the normal skin samples, corresponding to the up-regulated melanoma cells division rates ( Figure 1 ). Earlier studies have suggested that eIF6 is up-regulation in hepatocellular carcinoma, lung adenocarcinoma, and colorectal cancer ( 21 , 23 , 24 ). Similarly, the increased eIF6 expression levels also could be observed in LGG and PAAD using the GEPIA database analysis.…”

Section: Discussionmentioning

confidence: 99%

“…eIF6 has been reported as an essential regulator in liver hepatocellular carcinoma, colorectal carcinoma, and non-small cell lung carcinoma, respectively ( 21 , 23 , 24 ). Our study showed that the eIF6 up-regulation also occurs during melanoma tumorigenesis, which relates to a poorer prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, previous research found over-expression of eIF6 in ovarian cells and melanoma cell lines can effectively increase cell mobility and proliferation via CDC42 up-regulation ( 20 ). Furthermore, the increased eIF6 level has been reported to play a major role in association with poor prognostication of colorectal cancer, non-small cell lung carcinoma and malignant pleural mesothelioma ( 21 – 24 ). Thus, eIF6 is a promising diagnostic and prognostic candidate in melanoma.…”

Section: Introductionmentioning

confidence: 99%

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eIF6 as a Promising Diagnostic and Prognostic Biomarker for Poorer Survival of Cutaneous Melanoma

Zhang

Waheed²,

Armato³

et al. 2022

Front. Oncol.

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BackgroundSkin cutaneous melanoma (SKCM) is the deadliest skin cancer and has the most rapidly increasing incidences among all cancer types. Previous research elucidated that melanoma can only be successfully treated with surgical abscission in the early stage. Therefore, reliable and specific biomarkers are crucial to melanoma diagnosis since it often looks like nevi in the clinical manifestations. Moreover, identifying key genes contributing to melanoma progression is also highly regarded as a potential strategy for melanoma therapy. In this respect, translation initiator eIF6 has been proved as a pro-tumor factor in several cancers. However, the role of eIF6 in the skin cutaneous melanoma progression and its potential as a prognostic marker is still unexplored.MethodsThe immunochemical analysis of clinical specimens were served to assess eIF6 expression levels. Gene Expression Profiling Interactive Analysis (GEPIA) database consultations allowed us to find the survival rates of the eIF6-overexpressed patients. eIF6 cellular effects were evaluated in an eIF6-overexpressed A375 cell line constructed with a lentivirus. The analysis of down-stream effectors or pathways was conducted using C-Bioportal and STRING databases.ResultsOur results revealed that eIF6 was highly over-expressed in melanomas compared to normal skin specimens, and thus the abnormally high level of eIF6 can be a diagnostic marker for melanoma. The in silica analysis indicated that patients with eIF6 over-expression had lower survival rates than that low-expression in SKCM. Meanwhile, similar results also could be found in the other four types of cancers. In vitro, over-expression of eIF6 increased the proliferation and migration of melanoma cells. Correspondingly, pan-cancer clustering analysis indicated the expression level of intermediate filament proteins was correlated with that of eIF6 expression. In our study, all over-expressed keratin proteins, in accordance with over-expressed eIF6, had a negative correlation with melanoma prognosis. Moreover, the decreased methylation level of keratin genes suggested a new potential regulation mode of eIF6.ConclusionsThe up-regulated eIF6 could be a potential diagnostic and prognostic biomarker of melanoma. This study also provides insights into the potential role of eIF6 in pan-cancer epigenetic regulation.

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eIF6 Promotes Gastric Cancer Proliferation and Invasion by Regulating Cell Cycle

Huang,

Zhou,

Zheng

et al. 2024

Dig Dis Sci

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Objective To investigate the role and function of eIF6 in gastric cancer (GC). Methods The expression level of eIF6 in GC tissues and normal tissues was detected in different high-throughput sequencing cohorts. Survival analysis, gene differential analysis, and enrichment analysis were performed in the TCGA cohort. Biological networks centered on eIF6 were constructed through two different databases. Immunohistochemistry (IHC) and Western blot were used to detect protein expression of eIF6 , and qRT-PCR was used to detect eIF6 mRNA expression. The correlation between the expression of eIF6 in GC tissues and clinicopathological parameters of GC was analyzed. siRNA knockout of eIF6 was used to study the proliferation, migration, and invasion. The effects of eIF6 on cell cycle and Cyclin B1 were detected by flow cytometry and Western blot. Results eIF6 was significantly overexpressed in GC tissues and predicted poor prognosis. In addition, 113 differentially expressed genes were detected in cancer-related biological pathways and functions by differential analysis. Biological networks revealed interactions of genes and proteins with eIF6 . The expression intensity of eIF6 in cancer tissues was higher than that in adjacent tissues ( P = 0.0001), confirming the up-regulation of eIF6 expression in GC tissues. The expression level of eIF6 was statistically significant with pTNM stage ( P = 0.006). siRNA knockout of eIF6 significantly reduced the proliferation, colony formation, migration, and invasion ability of GC cells. Silencing of eIF6 also inhibited the cell cycle of GC cells in G2/M phase and decreased the expression level of CyclinB1. Conclusion Our study suggests that eIF6 is up-regulated in GC and may promote the proliferation, migration, and invasion of GC by regulating cell cycle.

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eIF6 promotes the malignant progression of human hepatocellular carcinoma via the mTOR signaling pathway

Cited by 18 publications

References 50 publications

UBE2O promotes hepatocellular carcinoma cell proliferation and invasion by regulating the AMPKα2/mTOR pathway

UBE2O promotes hepatocellular carcinoma cell proliferation and invasion by regulating the AMPKα2/mTOR pathway

eIF6 as a Promising Diagnostic and Prognostic Biomarker for Poorer Survival of Cutaneous Melanoma

eIF6 Promotes Gastric Cancer Proliferation and Invasion by Regulating Cell Cycle

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