Ubiquitination of IGF2BP3 by E3 ligase MKRN2 regulates the proliferation and migration of human neuroblastoma SHSY5Y cells

Jia, Caiwei; Tang, Hongli; Yang, Yan; Yuan, Shilin; Han, Tianting; Fang, Meimiao; Huang, Shuting; Hu, Ronggui; Li, Chuanyin; Geng, Wujun

doi:10.1016/j.bbrc.2020.05.112

Cited by 26 publications

(23 citation statements)

References 17 publications

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“…Next, we explored the mechanism of Smurf2 inhibiting the EMT process in HCC. TGF-β pathway plays an important role in EMT and metastasis of cancer cells [ 15 ]. Smurf2 is an E3 ubiquitin ligase, which plays a ubiquitination role by binding with the specific substrates, leading to ubiquitination degradation of the target proteins.…”

Section: Resultsmentioning

confidence: 99%

Smurf2 suppresses the metastasis of hepatocellular carcinoma via ubiquitin degradation of Smad2

Song

et al. 2022

Open Medicine

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Purpose Smurf2, one of C2-WW-HECT domain E3 ubiquitin ligases, is closely related to the development and progression in different cancer types, including hepatocellular carcinoma (HCC). This study aims to illustrate the expression and molecular mechanism of Smurf2 in regulating the progression of HCC. Methods The expression of Smurf2 in human HCC and adjacent non-tumor liver specimens was detected using tissue microarray studies from 220 HCC patients who underwent curative resection. The relationships of Smurf2 and HCC progression and survival were analyzed using the chi-square test, Kaplan–Meier analysis, and Cox proportional hazards model. For Smurf2 was low expression in HCC cell lines, Smurf2 overexpression cell lines were established. The effect of Smurf2 on cell proliferation and migration was detected by Cell Counting Kit-8 and colony formation assay, and the epithelial–mesenchymal transition (EMT) markers and its transcription factors were tested by immunoblotting. The interaction and ubiquitination of Smad2 by Smurf2 were detected by co-immunoprecipitation and immunoprecipitation assay. Finally, the effect of Smurf2 on HCC was verified using the mouse lung metastasis model. Results Smurf2 was downregulated in HCC tissues compared to that of corresponding non-tumor liver specimens. The low expression of Smurf2 in HCC was significantly associated with macrovascular or microvascular tumor thrombus and the impairment of overall survival and disease-free survival. In vitro and in vivo analysis showed that Smurf2 overexpression decreased the EMT potential of HCC cells by promoting the ubiquitination of Smad2 via the proteasome-dependent degradation pathway. Conclusion The expression of Smurf2 was downregulated in HCC specimens and affected the survival of patients. Smurf2 inhibited the EMT of HCC by enhancing Smad2 ubiquitin-dependent proteasome degradation.

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Section: Resultsmentioning

confidence: 99%

Smurf2 suppresses the metastasis of hepatocellular carcinoma via ubiquitin degradation of Smad2

Song

et al. 2022

Open Medicine

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“…The development of GC often involves ubiquitination [17,18]. We found that MKRN2 is poorly expressed in GC by The Cancer Genome Atlas (TCGA) public database.…”

Section: Discussionmentioning

confidence: 99%

MKRN2 inhibits the proliferation of gastric cancer by downregulating PKM2

Liu

Xiang

Guo

et al. 2022

Aging

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Cumulative evidence suggests that dysfunction of ubiquitinating enzymes is responsible for multiple types of diseases including cancer. However, what role the ubiquitinating enzyme plays in gastric cancer remains unknown. In this study, using bioinformatics analysis and a series of experimental analyses, we found that an E3 ubiquitin-protein, MKRN2 was down-regulated in gastric cancer tissues. Kaplan-Meier survival analysis showed the low MKRN2 expression significantly indicated poor prognosis. Overexpression of MKRN2 notably inhibited cell proliferation in vitro and in vivo. Conversely, knockdown of MKRN2 had the opposite effects in vitro. Additionally, the mechanical analysis indicated that MKRN2 promoted ubiquitination-mediated degradation of PKM2 and attenuated its effect on ERK. Overall, the present study suggests that MKRN2 may be a potential therapeutic target for gastric cancer.

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“…IGF2BP3 was first identified for its ability to promote the translation of IGF2 mRNA ( 34 ). The currently-identified mRNA targets of IGF2BP3 include CD44 ( 6 ), MMP9 ( 15 ), HMGA2 ( 35 ), and PDPN ( 36 ). This is the first study to investigate the biological functions of IGF2BP3 in mesothelioma cells.…”

Section: Discussionmentioning

confidence: 99%

Insulin-Like Growth Factor 2 mRNA Binding Protein 3 Promotes Cell Proliferation of Malignant Mesothelioma Cells by Downregulating p27Kip1

et al. 2022

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Malignant mesothelioma is a tumor with a poor prognosis, mainly caused by asbestos exposure and with no adequate treatment yet. To develop future therapeutic targets, we analyzed the microarray dataset GSE 29370 of malignant mesothelioma and reactive mesothelial hyperplasia, downloaded from the Gene Expression Omnibus (GEO) database. We identified insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) as one of the significantly upregulated genes in malignant mesothelioma. IGF2BP3 functions as an oncoprotein in many human cancers; however, to our knowledge, this is the first study on the biological function of IGF2BP3 in malignant mesothelioma cells. The knockdown of IGF2BP3 in malignant mesothelioma cells resulted in the suppression of cell proliferation with an increase in the proportion of cells in the G1 phase of the cell cycle. Furthermore, knockdown of IGF2BP3 inhibited cell migration and invasion. We focused on the cell cycle assay to investigate the role of IGF2BP3 in cell proliferation in malignant mesothelioma. Among the various proteins involved in cell cycle regulation, the expression of p27 Kip1 (p27) increased significantly upon IGF2BP3 knockdown. Next, p27 siRNA was added to suppress the increased expression of p27. The results showed that p27 knockdown attenuated the effects of IGF2BP3 knockdown on cell proliferation and G1 phase arrest. In conclusion, we found that IGF2BP3 promotes cell proliferation, a critical step in tumorigenesis, by suppressing the expression of p27 in malignant mesothelioma.

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Ubiquitination of IGF2BP3 by E3 ligase MKRN2 regulates the proliferation and migration of human neuroblastoma SHSY5Y cells

Cited by 26 publications

References 17 publications

Smurf2 suppresses the metastasis of hepatocellular carcinoma via ubiquitin degradation of Smad2

Smurf2 suppresses the metastasis of hepatocellular carcinoma via ubiquitin degradation of Smad2

MKRN2 inhibits the proliferation of gastric cancer by downregulating PKM2

Insulin-Like Growth Factor 2 mRNA Binding Protein 3 Promotes Cell Proliferation of Malignant Mesothelioma Cells by Downregulating p27Kip1

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