MicroRNA analysis of gastroenteropancreatic neuroendocrine tumors and metastases

Zimmermann, Nadine; Knief, Juliana; Kacprowski, Tim; Lazar-Karsten, Pamela; Keck, Tobias; Billmann, Franck; Schmid, Sebastian; Luley, Kim; Lehnert, Hendrik; Brabant, Georg; Thorns, Christoph

doi:10.18632/oncotarget.25357

Cited by 28 publications

(27 citation statements)

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“…This is also supported by the miR data in three ways. i) Expression in BON and QGP of miRs that inhibit migration, invasion, metastasis, and EMT [35,37,38,58,59]; ii) the identification in QGP but not BON cells of only two, weakly expressed miRs associated with metastases of panNET, miR-21 (RES = 9) and miR-let7b (RES = 6); and iii) the absence in the BON and QGP lines of mouse MLP and metastasis-specific miRs highly expressed in the majority of the samples in miR-cluster-1 and -2 from human panNET [12,60], and of miRs previously shown by us to be associated with NET metastases [11]. Together with the observation that BON and QGP cells display only low migratory in vitro and low-to-moderate metastatic activity in vivo, both lines are; therefore, likely to belong to the MLP-1 sub-subtype, where 5% of the tumors were associated with distant metastases vs. 45% of the MLP-2 subtype [12] (Figure 6).…”

Section: Discussionmentioning

confidence: 73%

“…In summary, BON and QGP cells express only few miRs specific to insulinomas or mature/functional β-cells and, if present, transcript levels are low, which is consistent with the lack of INS expression in both lines. High levels of miR-196a, miR-21, and miR-221 have been reported to be associated with tumor proliferation, advanced stage, metastases, recurrence, or reduced survival [11,47] and mucinous precursor lesions of PDAC [48]. Moreover, miR-664b identified in both BON and QGP cells regulates multiple aspects of pancreatic tumor development and progression and directly targets PAX6, which might help to explain the low expression of PAX6 in BON and QGP cells (see Figure 4A).…”

Section: Discussionmentioning

confidence: 99%

“…Although BON and QGP cells have been compared for the expression of some classical neuroendocrine markers to a recently established patient-derived panNET cell line (NT-3, [9]) and to panNET tissues [8], such a comparison has not yet been performed for other cellular features such as epithelial/mesenchymal differentiation, expression of genes governing immature and mature β-cell function and differentiation from pancreatic (endocrine) progenitors, or microRNA (miR) signatures. Earlier, we have performed miR profiling in GEP-NET and panNET tissues [10,11]; however, tumor tissues are heterogeneous with respect to cellular composition and, hence, their analysis does not allow for the identification of miRs expressed specifically by the tumor cell fraction.…”

Section: Introductionmentioning

confidence: 99%

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A Comprehensive Molecular Characterization of the Pancreatic Neuroendocrine Tumor Cell Lines BON-1 and QGP-1

Luley

Biedermann

Künstner

et al. 2020

Cancers

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Experimental models of neuroendocrine tumor disease are scarce, with only a few existing neuroendocrine tumor cell lines of pancreatic origin (panNET). Their molecular characterization has so far focused on the neuroendocrine phenotype and cancer-related mutations, while a transcription-based assessment of their developmental origin and malignant potential is lacking. In this study, we performed immunoblotting and qPCR analysis of neuroendocrine, epithelial, developmental endocrine-related genes as well as next-generation sequencing (NGS) analysis of microRNAs (miRs) on three panNET cell lines, BON-1, QGP-1, and NT-3. All three lines displayed a neuroendocrine and epithelial phenotype; however, while insulinoma-derived NT-3 cells preferentially expressed markers of mature functional pancreatic β-cells (i.e., INS, MAFA), both BON-1 and QGP-1 displayed high expression of genes associated with immature or non-functional β/δ-cells genes (i.e., NEUROG3), or pancreatic endocrine progenitors (i.e., FOXA2). NGS-based identification of miRs in BON-1 and QGP-1 cells revealed the presence of all six members of the miR-17-92 cluster, which have been implicated in β-cell function and differentiation, but also have roles in cancer being both oncogenic or tumor suppressive. Notably, both BON-1 and QGP-1 cells expressed several miRs known to be negatively associated with epithelial-mesenchymal transition, invasion or metastasis. Moreover, both cell lines failed to exhibit migratory activity in vitro.Cancers 2020, 12, 691 2 of 18 Taken together, NT-3 cells resemble mature functional β-cells, while both BON-1 and QGP-1 are more similar to immature/non-functional pancreatic β/δ-cells or pancreatic endocrine progenitors. Based on the recent identification of three transcriptional subtypes in panNETs, NT-3 cells resemble the "islet/insulinoma tumors" (IT) subtype, while BON-1 and QGP-1 cells were tentatively classified as "metastasis-like/primary" (MLP). Our results provide a comprehensive characterization of three panNET cell lines and demonstrate their relevance as neuroendocrine tumor models.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Comprehensive Molecular Characterization of the Pancreatic Neuroendocrine Tumor Cell Lines BON-1 and QGP-1

Luley

Biedermann

Künstner

et al. 2020

Cancers

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“…The microRNA (miRNA) landscape in GEP NEN may bear relevance to novel biomarkers [60][61][62]. Expression of miRNA in SBNEN tissue is deranged compared to normal SB [63], with 39 miRNAs showing significant deregulation (38 upregulated), miR-204-5p, miR-7-5p and miR-375 the most up-regulated and a 29 miRNA "signature" evident in SBNEN [64].…”

Section: Genetic and Epigenetic Landscape Of Sbnetmentioning

confidence: 99%

Neuroendocrine Neoplasms of the Small Bowel and Pancreas

et al. 2019

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The traditionally promulgated perspectives of neuroendocrine neoplasms (NEN) as rare, indolent tumours are blunt and have been outdated for the last 2 decades. Clear increments in their incidence over the past decades render them increasingly clinically relevant, and at initial diagnosis many present with nodal and/or distant metastases (notably hepatic). The molecular pathogenesis of these tumours is increasingly yet incompletely understood. Those arising from the small bowel (SB) or pancreas typically occur sporadically; the latter may occur within the context of hereditary tumour predisposition syndromes. NENs can also be associated with endocrinopathy of hormonal hypersecretion. Tangible advances in the development of novel biomarkers, functional imaging modalities and therapy are especially applicable to this sub-set of tumours. The management of SB and pancreatic neuroendocrine tumours (NET) may be challenging, and often comprises a multidisciplinary approach wherein surgical, medical, interventional radiological and radiotherapeu-tic modalities are implemented. This review provides a comprehensive overview of the epidemiology, pathophysiology, diagnosis and treatment of SB and pancreatic NETs. Moreover, we provide an outlook of the future in these tumour types which will include the development of precision oncology frameworks for individualised therapy, multi-analyte predictive biomarkers, artificial intelligence-derived clinical decision support tools and elucidation of the role of the microbiome in NEN development and clinical behaviour.According to SEER version 18, SBNEN and PanNEN incidences are currently estimated at 1.2 and 0.7 per 100,000, respectively [5]. The overall 20-year duration prevalence of all NEN is estimated at 171,321; SBNEN constituting 32,122 patients with 3-fold fewer PanNEN (10,707) [5]. Possible attributable factors for this increase evolving epidemiology include increased use of endoscopy and also improvements in the sensitivity of widely used imaging modalities, leading to increased detection of early-stage, asymptomatic disease [5].The median overall survival (OS) for NEN (irrespective of site and grade) is 9.3 years [5]. For SB (median OS: 14 years), this ranges from 70 months (advanced disease with distant metastases) to 170 months (localised disease) and from 30 months (Grade 3) to 160 months (Grade 1). For pancreas (median OS: 3.6 years): 21 months (advanced) to 235 months (localised disease) and from 15 months (Grade 3) to 140 months (Grade 1) [5].Multivariable analyses have identified that ethnicity, age, differentiation, stage and site all have statistically significant correlations with survival. In general, Caucasian ethnicity, age (< 50 years) and localised, well-differentiated NEN exhibit the best survival. SB tumour patients are approximately 1.5 times more likely to survive longer than those with PanNEN [19]. Many of these correlations are self-evident since they pertain to degree of malignancy, disease duration and patient performance status.OS (median 5-year) app...

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“…Further studies are required to evaluate the application of miRNAs as clinical and therapeutic markers in NENs. This issue is extensively reviewed in recent publications (Zatelli et al 2017, Zimmermann et al 2018, Rizzo & Meyer 2018, Panarelli et al 2019).…”

Section: Rna Markersmentioning

confidence: 99%

Neuroendocrine neoplasms: current and potential diagnostic, predictive and prognostic markers

Herrera‐Martínez

Hofland

Moreno

et al. 2019

Endocrine-Related Cancer

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Some biomarkers for functioning and non-functioning neuroendocrine neoplasms (NENs) are currently available. Despite their application in clinical practice, results should be interpreted cautiously. Considering the variable sensitivity and specificity of these parameters, there is an unmet need for novel biomarkers to improve diagnosis and predict patient outcome. Nowadays, several new biomarkers are being evaluated and may become future tools for the management of NENs. These biomarkers include (1) peptides and growth factors; (2) DNA and RNA markers based on genomics analysis, for example, the so-called NET test, which has been developed for analyzing gene transcripts in circulating blood; (3) circulating tumor/endothelial/progenitor cells or cell-free tumor DNA, which represent minimally invasive methods that would provide additional information for monitoring treatment response and (4) improved imaging techniques with novel radiolabeled somatostatin analogs or peptides. Below we summarize some future directions in the development of novel diagnostic and predictive/prognostic biomarkers in NENs. This review is focused on circulating and selected tissue markers.

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MicroRNA analysis of gastroenteropancreatic neuroendocrine tumors and metastases

Cited by 28 publications

References 42 publications

A Comprehensive Molecular Characterization of the Pancreatic Neuroendocrine Tumor Cell Lines BON-1 and QGP-1

A Comprehensive Molecular Characterization of the Pancreatic Neuroendocrine Tumor Cell Lines BON-1 and QGP-1

Neuroendocrine Neoplasms of the Small Bowel and Pancreas

Neuroendocrine neoplasms: current and potential diagnostic, predictive and prognostic markers

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