Enhanced IMP3 Expression Activates NF-кB Pathway and Promotes Renal Cell Carcinoma Progression

Pei, Xuelian; Li, Muhan; Zhan, Jun; Yu, Yu; Wei, Xiaofan; Guan, Lina; Aydın, Hakan; Elson, Paul; Zhou, Ming; He, Huiying; Zhang, Hongquan

doi:10.1371/journal.pone.0124338

Cited by 40 publications

(44 citation statements)

References 32 publications

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“…Our findings in glioma cells with IMP3 overexpression and silencing unequivocally establish IMP3 as a positive modulator of NF-κB signalling by increasing the translation of p65 transcript. These results are in coherence with the observations made by Pei et al, where they have shown that IMP3 activates NF-κB pathway and contributes to migration of renal cell carcinoma cells [52]. Our p65 rescue experiment in IMP3 depleted U138 glioma cells clearly reflects the importance of the molecule downstream to IMP3 in imparting migratory potential to these cells.…”

Section: Discussionsupporting

confidence: 93%

IGF2 mRNA binding protein 3 (IMP3) promotes glioma cell migration by enhancing the translation of RELA/p65

et al. 2017

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The diffusely infiltrative nature of glioblastoma (GBM) makes them highly recurrent. IGF2 mRNA-binding protein 3 (IMP3), a GBM upregulated RNA binding protein, promotes glioma cell migration. An integrative bioinformatics analysis identified p65 (RELA), a subunit of NF-κB heterodimer as a target and an important mediator of IMP3 promoted glioma cell migration. IMP3 increased p65 protein levels without any change in p65 transcript levels, but promoted its polysome association. RIP-PCR demonstrated the binding of IMP3 to p65 transcript. UV crosslinking experiments with in vitro transcribed RNA confirmed the specific and direct binding of IMP3 to sites on p65 3′UTR. Further, IMP3 induced luciferase activity from p65 3′UTR reporter carrying wild type sites but not mutated sites. Exogenous overexpression of p65 from a 3′UTR-less construct rescued the reduced migration of glioma cells in IMP3 silenced condition. In addition, IMP3 silencing inhibited glioma stem-like cell maintenance and migration. The exogenous overexpression of 3′UTR-less p65 significantly alleviated the inhibition of neurosphere formation observed in IMP3 silenced glioma stem-like cells. Further, we show that IMP3 is transcriptionally activated by NF-κB pathway indicating the presence of a positive feedback loop between IMP3 and p65. This study establishes p65 as a novel target of IMP3 in increasing glioma cell migration and underscores the significance of IMP3-p65 feedback loop for therapeutic targeting in GBM.

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Section: Discussionsupporting

confidence: 93%

IGF2 mRNA binding protein 3 (IMP3) promotes glioma cell migration by enhancing the translation of RELA/p65

et al. 2017

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“…It had been reported that knockdown of IMP3 in cervical cancer, breast cancer and melanoma cell lines could reduce cell migration and invasiveness [ 38 – 40 ]. In renal cell carcinoma, IMP3 can also promote cell migration and invasion by activation of NF-κB pathway [ 41 ]. As recently reported, knockdown of IMP3 decreased cell proliferation, migration, and invasion, and increased the sensitivity to platinum in ovarian cancer through increased expression of hCTR1 [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Clear cell carcinomas of the ovary: a mono-institutional study of 73 cases in China with an analysis of the prognostic significance of clinicopathological parameters and IMP3 expression

Zhang

Cheng

et al. 2016

Diagn Pathol

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BackgroundOvarian clear cell carcinoma (CCC) is an uncommon subtype of ovarian epithelial tumor. The prognostic significance of its clinicopathological parameters is discordant, with the exception of stage as the adverse prognostic factor. The present study aimed to evaluate the prognostic significance of its clinicopathological characteristics and the expression of IMP3 (Insulin-like growth factor-II mRNA-binding protein 3, IMP3 or IGF2BP3) in Chinese patients with primary pure CCC.MethodsWe collected clinicopathological data from 73 cases with a minimum of 5 years of follow-up and evaluated the expression of IMP3 by immunohistochemistry.ResultsIn total, 49.3 % of the patients were in stage I. Advanced stages were closely related to poor prognosis of disease-free survival (DFS) and overall survival (OS) (P < 0.005). Patients with CCC coexisting with endometriosis tended to be younger and to have unilateral involvement but did not exhibit differences in prognosis compared with patients with CCC without endometriosis. Other histological features such as growth pattern, mitosis, and necrosis did not have prognostic significance. IMP3 was positive in 63 % of patients (46 of 73 cases); Thus, positive expression of IMP3 is an adverse prognostic marker in terms of OS (P = 0.012), even in stage I patients (P = 0.038).ConclusionsThe present study demonstrates that IMP3 expression is a prognostic marker, with the exception of stage. IMP3 represents a biomarker of unfavorable prognosis even in stage I patients.

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“…IMP3 is thought of as a bona fide oncofetal protein that is overexpressed and is involved in cell proliferation, migration, and invasion in several kinds of tumors ( 18 , 23 , 28 , 29 ). In regard to skin squamous neoplasms, the role of IMP3 in cutaneous SCC, using various cell biological and molecular biological approaches, has not been well studied.…”

Section: Discussionmentioning

confidence: 99%

“…Other groups have described the mechanism of cell proliferation and invasion of IMP3 expression in cells. Recent studies have revealed that IMP3 promoted the progression of melanoma by regulating high mobility group AT-hook 2 (HMGA2) ( 18 ), the cell migration of renal cell carcinoma by activation of the NF-κB pathway ( 28 ), cell invasion and migration after epithelial to mesenchymal transition (EMT) ( 29 ), and matrix adhesion, cell motility and invasion of pancreatic carcinoma by enhancing CD44 and the transcription of kinesin KIF11 expression ( 23 ).…”

Section: Discussionmentioning

confidence: 99%

Insulin-like growth factor 2 mRNA-binding protein-3 as a marker for distinguishing between cutaneous squamous cell carcinoma and keratoacanthoma

Kanzaki

Kudo

Ansai

et al. 2016

International Journal of Oncology

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In the histopathological diagnosis of cutaneous tumors, the differential diagnosis of squamous cell carcinoma (SCC) with crateriform architecture and keratoacanthoma (KA) is often difficult so an accurate understanding of the biological features and the identification of reliable markers of SCC and KA are crucial issues. Insulin-like growth factor 2 mRNA-binding protein-3 (IGF2BP3, also known as IMP3) is thought of as a bona fide oncofetal protein, which is overexpressed and is involved in cell proliferation, migration, and invasion in several kinds of tumors. However, the role of IMP3 in cutaneous SCC and KA has not been well studied. Therefore, we focused on studying the biological functions of IMP3 in SCC and KA. In human skin SCC cell lines, HSC-1 and HSC-5, and the human keratinocyte cell line, HaCaT, IMP3 mRNA levels were significantly higher than that of normal human skin. The knockdown of IMP3 expression reduced the proliferation of HSC-1, and significantly reduced invasion by HSC-1 and HSC-5. In contrast, the knockdown of IMP3 did not significantly affect invasion by HaCaT cells. In immunohistochemical studies of SCC and KA tissues, the Ki-67 labeling index (LI) of the suprabasal cell layer was significantly higher in SCC, compared with KA tissues and the tumor-free margin (TFM) adjacent to SCC and KA. Most SCC tissues stained strongly positive for IMP3, but KA tissues and TFM were mostly negative for IMP3. The Ki-67 LI of the IMP3-positive group was significantly higher than that of the IMP3-negative group in the suprabasal cell layer of SCC. These results suggest that IMP3 plays an important role in proliferation and, more significantly, in the invasion of SCC, and may be a suitable marker for the histopathological diagnosis of SCC with a crateriform architecture and KA. Furthermore, IMP3 may potentially be a new therapeutic target for SCC.

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Enhanced IMP3 Expression Activates NF-кB Pathway and Promotes Renal Cell Carcinoma Progression

Cited by 40 publications

References 32 publications

IGF2 mRNA binding protein 3 (IMP3) promotes glioma cell migration by enhancing the translation of RELA/p65

IGF2 mRNA binding protein 3 (IMP3) promotes glioma cell migration by enhancing the translation of RELA/p65

Clear cell carcinomas of the ovary: a mono-institutional study of 73 cases in China with an analysis of the prognostic significance of clinicopathological parameters and IMP3 expression

Insulin-like growth factor 2 mRNA-binding protein-3 as a marker for distinguishing between cutaneous squamous cell carcinoma and keratoacanthoma

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