Roles of miR-196a on gene regulation of neuroendocrine tumor cells

Li, Su-Chen; Shi, Hao; Khan, Mohid S.; Caplin, Martyn; Meyer, Tim; Öberg, Kjell; Giandomenico, Valeria

doi:10.1016/j.mce.2015.06.003

Cited by 13 publications

(12 citation statements)

References 36 publications

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“…For this purpose we chose the two intestinal neuroendocrine cell lines STC‐1 and CNDT2.5. Even if the neuroendocrine authenticity of CNDT2.5 cells has been discussed, they remain one of the rare human NET cell lines of intestinal origin and have been widely used as an intestinal NET model in several studies . Downregulation of NRP‐2 in STC‐1 cells did not have any in vitro effects on cell viability or proliferation.…”

Section: Discussionmentioning

confidence: 98%

Neuropilin‐2 contributes to tumor progression in preclinical models of small intestinal neuroendocrine tumors

Bollard

Patte

Radkova

et al. 2019

The Journal of Pathology

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The identification of novel regulators of tumor progression is a key challenge to gain knowledge on the biology of small intestinal neuroendocrine tumors (SI‐NETs). We recently identified the loss of the axon guidance protein semaphorin 3F as a protumoral event in SI‐NETs. Interestingly the expression of its receptor neuropilin‐2 (NRP‐2) was still maintained. This study aimed at deciphering the potential role of NRP‐2 as a contributor to SI‐NET progression. The role of NRP‐2 in SI‐NET progression was addressed using an approach integrating human tissue and serum samples, cell lines and in vivo models. Data obtained from human SI‐NET tissues showed that membranous NRP‐2 expression is present in a majority of tumors, and is correlated with invasion, metastatic abilities, and neovascularization. In addition, NRP‐2 soluble isoform was found elevated in serum samples from metastatic patients. In preclinical mouse models of NET progression, NRP‐2 silencing led to a sustained antitumor effect, partly driven by the downregulation of VEGFR2. In contrast, its ectopic expression conferred a gain of aggressiveness, driven by the activation of various oncogenic signaling pathways. Lastly, NRP‐2 inhibition led to a decrease of tumor cell viability, and sensitized to therapeutic agents. Overall, our results point out NRP‐2 as a potential therapeutic target for SI‐NETs, and will foster the development of innovative strategies targeting this receptor. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 98%

Neuropilin‐2 contributes to tumor progression in preclinical models of small intestinal neuroendocrine tumors

Bollard

Patte

Radkova

et al. 2019

The Journal of Pathology

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“…There is accumulating evidence that the HCV core protein can exert a regulatory function through the expression of microNAs (19). miR-196a has been shown to be crucial in normal cell differentiation and proliferation, and in the tumorigenesis of various types of cancer (20)(21)(22)(23). The upregulation of miR-196a correlates with aggressive progression and unfavourable prognoses in colorectal cancer, gastric cancer, non-small cell lung cancer, osteosarcoma and other types of cancer (24)(25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

HCV core protein-induced upregulation of microRNA-196a promotes aberrant proliferation in hepatocellular carcinoma by targeting FOXO1

Yue

et al. 2016

Molecular Medicine Reports

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The hepatitis C virus (HCV) core protein is critical in the development of hepatocellular carcinoma (HCC). Investigations on HCC have previously focused on microRNAs, a class of small non‑coding RNAs, which are crucial in cancer development and progression. The present study aimed to investigate whether microRNA (miR)‑196a is aberrantly regulated by the HCV core protein, and whether miR‑196a is involved in the regulation of the aberrant proliferation of HCV‑HCC cells. In the study, miRNA expression was detected by quantitative polymerase chain reaction analysis. An Ad‑HCV core adenovirus was constructed and cell proliferation was measured using a Cell Counting Kit-8 assay and a cell cycle assay following infection. The results of the present study demonstrated that the HCV core protein increased the expression of miR‑196a, and that overexpression of miR‑196a in the HepG2 and Huh‑7 HCC cell lines promoted cell proliferation by inducing the G1‑S transition. Furthermore, the present study demonstrated that forkhead box O1 (FOXO1) was directly regulated by miR‑196a, and was essential in mediating the biological effects of miR‑196a in HCC. The overexpression of FOXO1 markedly reversed the effect of miR‑196a in HCC cell proliferation. Taken together, the data obtained in the present study provided compelling evidence that elevated expression levels of miR‑196a by the HCV core protein can function as an onco‑microRNA during HCV‑induced cell proliferation by downregulating the expression of FOXO1, indicating a potential novel therapeutic target for HCV-related HCC.

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“…Based upon reports of MiR-196a dysregulation in SBNET [58] (and lung NET [59]), studies were undertaken in which MiR-196a was silenced in CNDT2.5 (midgut NET) and NCI-H727 (bronchial NET) cell lines to assess whether it was a negative regulator of its predicted target genes involved in multicellular organismal development ( HOXA9 and HOXB7 ) or in the Wnt signaling pathway ( LRP4 and RSPO2 ). All target genes and proteins, as well as 6 downstream MiR-196 genes, were significantly upregulated in the silenced NET cells, demonstrating no relationship between miRNA and target mRNAs.…”

Section: Tissue Expression Of Mirnas In Gep-netsmentioning

confidence: 99%

“…Additionally, the effect of MiR-196a silencing on cell proliferation was evaluated by the MTT assay, showing no significant regulation. Based on the study results, a potential regulatory effect of MiR-196a on cell growth control in these model cell lines was excluded [59]. …”

Section: Tissue Expression Of Mirnas In Gep-netsmentioning

confidence: 99%

A Comprehensive Assessment of the Role of miRNAs as Biomarkers in Gastroenteropancreatic Neuroendocrine Tumors

et al. 2018

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Background/Aims: A key issue in neuroendocrine neoplasia management is the identification of blood signatures that specifically define the activity of a cancer or local tumor microenvironment. MicroRNAs (miRNAs) may represent such a candidate. To evaluate their clinical utility as biomarkers in gastroenteropancreatic neuroendocrine tumors (GEP-NETs), we assessed their expression in tissue and blood. Methods: A systematic review of PubMed was undertaken to identify studies investigating miRNAs in GEP-NETs and their utility as blood or tissue biomarkers. Results: Twenty-two studies using a range of methodologies with different normalization protocols were identified: tumor – gastric NET type 1 (n = 1 study: MiR-222, regulates p27KIP1), pancreatic (n = 6: MiR-21 [inflammatory marker, oncogene] and MiR-144 [PI₃K/AKT signaling], both up- and downregulated depending on the method), small intestinal (n = 7: no consistent signature), and colorectal (n = 3: no consistent signature); blood – gastric NET type 1 (n = 1: MiR-222), pancreatic (n = 3: MiR-21), and small intestinal (n = 3: no consistent signature). The studies all included heterogeneous cohorts, were insufficiently powered, and utilized different methodologies, and age- and gender-matched controls were not used. Different miRNA isolation methods and detection protocols resulted in inconsistent expression comparing tumor and blood. A scientific discrepancy was the downregulated expression of some circulating candidates compared to tissue levels, suggesting methodological issues or physiological responses to the tumor. Both are of concern in defining the biometrics of a marker. Conclusions: A potential biomarker for GEP-NETs included MiR-21 (small bowel and pancreas), but this epithelial tumor marker requires prospective validation. Overall, significant scientific investigation remains to identify and demonstrate neuroendocrine specificity and to validate candidate miRNA biomarkers.

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Roles of miR-196a on gene regulation of neuroendocrine tumor cells

Cited by 13 publications

References 36 publications

Neuropilin‐2 contributes to tumor progression in preclinical models of small intestinal neuroendocrine tumors

Neuropilin‐2 contributes to tumor progression in preclinical models of small intestinal neuroendocrine tumors

HCV core protein-induced upregulation of microRNA-196a promotes aberrant proliferation in hepatocellular carcinoma by targeting FOXO1

A Comprehensive Assessment of the Role of miRNAs as Biomarkers in Gastroenteropancreatic Neuroendocrine Tumors

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