The microtubule-associated protein MAPRE2 is involved in perineural invasion of pancreatic cancer cells

Abiatari, Ivane; Gillen, Sonja; DeOliveira, Tiago; Klose, Theresa; Kong, Bo; Giese, Nathalia A.; Friess, Helmut; Kleeff, Jörg

doi:10.3892/ijo_00000426

Cited by 11 publications

(2 citation statements)

References 31 publications

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“…It has been reported that MAPRE2 is overexpressed in hepatocellular carcinoma (35) and esophageal squamous cell carcinoma (36); thus, MAPRE2 might be involved in tumorigenesis and promotion of tumor cell growth through Wnt signaling pathway or Aurora-B activation (37,38). A study by Abiatari et al (39) demonstrated that overexpression of MAPRE2 is associated with decreased survival and perineural infiltration in pancreatic cancer patients. Therefore, MAPRE2 overexpression in various malignant tumors is positively correlated with tumor growth, nerve infiltration, and poor prognosis.…”

Section: Figure 6 |mentioning

confidence: 99%

WDHD1 Leads to Cisplatin Resistance by Promoting MAPRE2 Ubiquitination in Lung Adenocarcinoma

Gong

Xiao

et al. 2020

Front. Oncol.

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Ubiquitin ligases have been shown to regulate drug sensitivity. This study aimed to explore the role of the ubiquitin ligase WD repeat and HMG-box DNA binding protein 1 (WDHD1) in regulating cisplatin sensitivity in lung adenocarcinoma (LUAD). A quantitative analysis of the global proteome identified differential protein expression between LUAD A549 cells and the cisplatin-resistant strain A549/DDP. Public databases revealed the relationship between ubiquitin ligase expression and the prognosis of patients with LUAD. Quantitative real-time polymerase chain reaction and Western blotting were used to estimate the WDHD1 expression levels. Analysis of public databases predicted the substrate of WDHD1. Western blotting detected the effect of WDHD1 on microtubule-associated protein RP/EB family member 2 (MAPRE2) and DSTN. Functional analysis of MAPRE2 verified the interaction between WDHD1 and MAPRE2, as well as the interacting sites by methyl-thiazolyl-tetrazolium assay and flow cytometry, immunoprecipitation, protein stability, and immunofluorescence. Cell and animal experiments confirmed the effect of WDHD1 and MAPRE2 on cisplatin sensitivity in LUAD. Clinical data evaluated the impact of WDHD1 expression level on cisplatin sensitivity. Quantitative analysis of the global proteome revealed ubiquitin-dependent protein catabolism to be more active in A549/DDP cells than in A549 cells. WDHD1 expression was higher in A549/DDP cells than in A549 cells, and knocking out WDHD1 increased the sensitivity of A549/DDP cells to cisplatin. WDHD1 overexpression negatively correlated with the overall survival of LUAD patients. We observed that MAPRE2 was upregulated when WDHD1 was knocked out. A MAPRE2 knockout in A549 cells resulted in increased cell viability while decreasing apoptosis when the A549 cells exposed to cisplatin. WDHD1 and MAPRE2 were found to interact in the nucleus, and WDHD1 promoted the ubiquitination of MAPRE2. Following cisplatin exposure, the WDHD1 and MAPRE2 knockout groups facilitated cell proliferation and migration, inhibited apoptosis in A549/DDP cells, decreased apoptosis, and increased tumor size and growth rate in animal experiments. Gong et al. Chemotherapy Resistance of Lung Adenocarcinoma Immunohistochemistry showed that Ki67 levels increased, and levels of apoptotic indicators significantly decreased in the WDHD1 and MAPRE2 knockout groups. Clinical data confirmed that WDHD1 overexpression negatively correlated with cisplatin sensitivity. Thus, the ubiquitin ligase WDHD1 induces cisplatin resistance in LUAD by promoting MAPRE2 ubiquitination.

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Section: Figure 6 |mentioning

confidence: 99%

WDHD1 Leads to Cisplatin Resistance by Promoting MAPRE2 Ubiquitination in Lung Adenocarcinoma

Gong

Xiao

et al. 2020

Front. Oncol.

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“…Interestingly, we also found that the expression level of EB2 in SLHCC was lower than that in NHCC, which is consistent with our previous studies demonstrating distinct molecular characteristics between SLHCC and NHCC [21,[37][38][39], implying the potential of EB2 to determine the malignant behaviors and to distinguish different subtypes of HCC. Though EB2 was previously reported to be markedly up-regulated in highly nerve invasive pancreatic cancer cells [40], its biological function in cancer is still poorly defined. Here, we revealed that overexpression of EB2 significantly promoted HCC cell proliferation, invasion and metastasis in vitro and in vivo, whereas knockdown of EB2 inhibited these processes.…”

Section: Src Kinase Is Responsible For Eb2-mediated Erk Activationmentioning

confidence: 99%

EB2 promotes hepatocellular carcinoma proliferation and metastasis via MAPK/ERK pathway by modulating microtubule dynamics

Zhong

et al. 2021

Clinical Science

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Metastasis is the main cause of poor postoperative survival of hepatocellular carcinoma (HCC) patients. Cytoskeleton rearrangement is a key event in cancer metastasis. However, the significance of microtubule (MT), one of the core components of cytoskeleton, in this process is only beginning to be revealed. Here, we found that end-binding protein 2 (EB2), a MT dynamics regulator, is highly expressed in HCC and predicts poor prognosis of HCC patients. Functional studies show that EB2 overexpression promotes HCC proliferation, invasion and metastasis in vitro and in vivo, while EB2 knockdown has opposite results. Mechanistically, EB2 mediates MTs destabilization, increases Src activity, and thus facilitates extracellular signal-regulated kinase (ERK) signaling activation, which could in turn promotes EB2 expression in HCC, eventually resulting in enhanced HCC proliferation, invasion and metastasis. Furthermore, U0126, a specific ERK inhibitor, could effectively inhibit EB2-mediated HCC proliferation and metastasis in vitro and in vivo. In conclusion, EB2 coordinates MT cytoskeleton and intracellular signal transduction, forming an EB2-MT-ERK positive feedback loop, to facilitate HCC proliferation, invasion and metastasis. EB2 could serve as a promising prognostic biomarker and potential therapeutic target for HCC; HCC patients with high EB2 expression may benefit from treatment with ERK inhibitors.

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Comparative differential proteomic profiles of nonfailing and failing hearts after in vivo thoracic aortic constriction in mice overexpressing FKBP12.6

et al. 2013

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Chronic pressure overload (PO) induces pathological left ventricular hypertrophy (LVH) leading to congestive heart failure (HF). Overexpression of FKBP12.6 (FK506-binding protein [K]) in mice should prevent Ca2+-leak during diastole and may improve overall cardiac function. In order to decipher molecular mechanisms involved in thoracic aortic constriction (TAC)-induced cardiac remodeling and the influence of gender and genotype, we performed a proteomic analysis using two-dimensional differential in-gel electrophoresis (2D-DIGE), mass spectrometry, and bioinformatics techniques to identify alterations in characteristic biological networks. Wild-type (W) and K mice of both genders underwent TAC. Thirty days post-TAC, the altered cardiac remodeling was accompanied with systolic and diastolic dysfunction in all experimental groups. A gender difference in inflammatory protein expression (fibrinogen, α-1-antitrypsin isoforms) and in calreticulin occurred (males > females). Detoxification enzymes and cytoskeletal proteins were noticeably increased in K mice. Both non- and congestive failing mouse heart exhibited down- and upregulation of proteins related to mitochondrial function and purine metabolism, respectively. HF was characterized by a decrease in enzymes related to iron homeostasis, and altered mitochondrial protein expression related to fatty acid metabolism, glycolysis, and redox balance. Moreover, two distinct differential protein profiles characterized TAC-induced pathological LVH and congestive HF in all TAC mice. FKBP12.6 overexpression did not influence TAC-induced deleterious effects. Huntingtin was revealed as a potential mediator for HF. A broad dysregulation of signaling proteins associated with congestive HF suggested that different sets of proteins could be selected as useful biomarkers for HF progression and might predict outcome in PO-induced pathological LVH.

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The microtubule-associated protein MAPRE2 is involved in perineural invasion of pancreatic cancer cells

Cited by 11 publications

References 31 publications

WDHD1 Leads to Cisplatin Resistance by Promoting MAPRE2 Ubiquitination in Lung Adenocarcinoma

WDHD1 Leads to Cisplatin Resistance by Promoting MAPRE2 Ubiquitination in Lung Adenocarcinoma

EB2 promotes hepatocellular carcinoma proliferation and metastasis via MAPK/ERK pathway by modulating microtubule dynamics

Comparative differential proteomic profiles of nonfailing and failing hearts after in vivo thoracic aortic constriction in mice overexpressing FKBP12.6

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