Nuclear <scp>AREG</scp> affects a low‐proliferative phenotype and contributes to drug resistance of melanoma

Seefried, Felix; Haller, Lucia; Fukuda, Shinji; Thongmao, Aranya; Schneider, Nadja; Utikal, Jochen; Higashiyama, Shigeki; Bosserhoff, Anja‐Katrin; Kuphal, Silke

doi:10.1002/ijc.34254

Cited by 7 publications

(8 citation statements)

References 55 publications

(168 reference statements)

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“…All cell lines (Table 1 ) were incubated at 37 °C in an 8 % CO 2 humidified atmosphere [ 40 ]. All human cell lines have been authenticated using Short Tandem Repeat (STR) profiling within the last three years (DSMZ, Braunschweig, Germany and Multiplexion, Heidelberg, Germany).…”

Section: Methodsmentioning

confidence: 99%

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NRN1 interacts with Notch to increase oncogenic STAT3 signaling in melanoma

Devitt,

Westphal,

Pieger

et al. 2024

Cell Commun Signal

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Background Melanoma is a highly heterogeneous cancer, in which frequent changes in activation of signaling pathways lead to a high adaptability to ever changing tumor microenvironments. The elucidation of cancer specific signaling pathways is of great importance, as demonstrated by the inhibitor of the common BrafV600E mutation PLX4032 in melanoma treatment. We therefore investigated signaling pathways that were influenced by neurotrophin NRN1, which has been shown to be upregulated in melanoma. Methods Using a cell culture model system with an NRN1 overexpression, we investigated the influence of NRN1 on melanoma cells’ functionality and signaling. We employed real time cell analysis and spheroid formation assays, while for investigation of molecular mechanisms we used a kinase phosphorylation kit as well as promotor activity analysis followed by mRNA and protein analysis. Results We revealed that NRN1 interacts directly with the cleaved intracellular domain (NICD) of Notch1 and Notch3, causing a potential retention of NICD in the cytoplasm and thereby reducing the expression of its direct downstream target Hes1. This leads to decreased sequestration of JAK and STAT3 in a Hes1-driven phosphorylation complex. Consequently, our data shows less phosphorylation of STAT3 while presenting an accumulation of total protein levels of STAT3 in association with NRN1 overexpression. The potential of the STAT3 signaling pathway to act in both a tumor suppressive and oncogenic manner led us to investigate specific downstream targets – namely Vegf A, Mdr1, cMet - which were found to be upregulated under oncogenic levels of NRN1. Conclusions In summary, we were able to show that NRN1 links oncogenic signaling events between Notch and STAT3 in melanoma. We also suggest that in future research more attention should be payed to cellular regulation of signaling molecules outside of the classically known phosphorylation events. Graphical Abstract

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Section: Methodsmentioning

confidence: 99%

“…The staining procedure was previously described [ 40 ]. Used antibodies and concentrations are listed in Table 4 .…”

Section: Methodsmentioning

confidence: 99%

NRN1 interacts with Notch to increase oncogenic STAT3 signaling in melanoma

Devitt,

Westphal,

Pieger

et al. 2024

Cell Commun Signal

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“…Immunohistochemical analysis of patient-derived human cutaneous malignant melanoma tissue samples was performed as described previously [ 33 ]. Therefore, formalin fixed, paraffin embedded human cutaneous melanoma biopsies were microdissected (5 µm) and stained with a MAGOH/MAGOHB antibody using a 1:50 dilution (sc-56724, Santa Cruz Biotechnology, Dallas, TX, USA).…”

Section: Methodsmentioning

confidence: 99%

MAGOH and MAGOHB Knockdown in Melanoma Cells Decreases Nonsense-Mediated Decay Activity and Promotes Apoptosis via Upregulation of GADD45A

Soederberg

Meißgeier

Bosserhoff

et al. 2022

Cells

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Cutaneous malignant melanoma is a highly proliferative and aggressive skin cancer with a steadily increasing incidence and a low long-term survival rate after metastatic progression. The protein MAGOH and its highly identical homologue MAGOHB are core components of the exon junction complex (EJC), which regulates splicing, stability and translation of mRNAs. The EJC, and especially MAGOH, has been shown to be involved in the development and progression of several cancers. In melanoma, the expression and function of both homologues remain essentially unexplored. This study identifies high MAGOH and MAGOHB protein expression in cutaneous melanoma cell lines and patient derived tissue samples. An siRNA-mediated knockdown of MAGOH significantly inhibits melanoma cell proliferation. The loss of MAGOH does not affect cell cycle progression, but induces apoptosis, an effect that is enhanced by a simultaneous knockdown of MAGOH and MAGOHB. MAGOH and MAGOHB do not influence the expression of the pro-apoptotic protein Bcl-XS or exon skipping. However, the knockdown of MAGOH and MAGOHB strongly decreases nonsense-mediated decay (NMD) activity, leading to an upregulation of the pro-apoptotic protein GADD45A. In conclusion, simultaneous inhibition of MAGOH and MAGOHB expression substantially affects cell survival, indicating both MAGOH homologues as promising new targets for the treatment of melanoma.

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“…It is expressed in a variety of tumors, including ovarian, breast, gastric, colon, and PCs. According to studies investigating both hepatocellular and melanoma carcinoma 4 , 5 , AREG plays a crucial role in cell invasion and metastasis, and AREG promotes ovarian cancer stem cells and drug resistance through the AREG-EGFR-ERK pathway 6 . AREG is involved in regulating the proliferation and migration of erbB2- and HER2-positive breast cancer cells 7 .…”

Section: Introductionmentioning

confidence: 99%

miR-33a-3p regulates METTL3-mediated AREG stability and alters EMT to inhibit pancreatic cancer invasion and metastasis

Su,

Lai,

Tao

et al. 2023

Sci Rep

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Recent studies have shown that amphoteric regulatory protein (AREG), a member of the epidermal growth factor (EGF) family, is expressed in many cancers and is an independent prognostic indicator for patients with pancreatic cancer, but whether AREG is regulated at the epigenetic level to promote the development of pancreatic cancer (PC) has not been elucidated. Our results support the notion that AREG is overexpressed in pancreatic cancer tissues and cell lines. Functionally, the deletion of AREG impedes pancreatic cancer (PC) cell proliferation, migration, and invasion. In addition, we identified and validated that methyltransferase-like 3 (METTL3) induced the m6A modification on AREG and facilitated the stability of AREG mRNA after sequencing. Additionally, we obtained experimental evidence that miR-33a-3p targets and inhibits METTL3 from taking action, as predicted by using the miRDB and RNAinter. Remediation experiments showed that miR-33a-3p inhibits PC progression through METTL3. In summary, this research reveals that miR-33a-3p inhibits m6A-induced stabilization of AREG by targeting METTL3, which plays a key role in the aggressive progression of PC. AREG could be a potential target for PC treatment.

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Nuclear AREG affects a low‐proliferative phenotype and contributes to drug resistance of melanoma

Cited by 7 publications

References 55 publications

NRN1 interacts with Notch to increase oncogenic STAT3 signaling in melanoma

NRN1 interacts with Notch to increase oncogenic STAT3 signaling in melanoma

MAGOH and MAGOHB Knockdown in Melanoma Cells Decreases Nonsense-Mediated Decay Activity and Promotes Apoptosis via Upregulation of GADD45A

miR-33a-3p regulates METTL3-mediated AREG stability and alters EMT to inhibit pancreatic cancer invasion and metastasis

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