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Nesfatin-1/Nucleobindin-2 enhances cell migration, invasion, and epithelial-mesenchymal transition via LKB1/AMPK/TORC1/ZEB1 pathways in colon cancer.

ABSTRACT: Recent studies indicate that a high level of nesfatin-1/Nucleobindin-2 (NUCB-2) is associated with poor outcome and promotes cell migration in breast cancer and prostate cancer. However, the role of NUCB2 is not well known in colon cancer. In this study, NUCB-2 level in colon cancer tissue was higher than that in non-tumor tissue. Suppression of NUCB-2 in a colon cancer cell line SW620 inhibited migration and invasion. The microarray analysis showed that low expression level of transcription factor ZEB1 in NUCB-2 knockdowned SW620 cells. In addition, expression level of epithelial-mesenchymal transition (EMT)-related molecules including N-cadherin, E-cadherin, ?-catenin, Slug and Twist was affected by NUCB-2 suppression and ZEB1-denepdent pathway. The signaling pathway liver kinase B1(LKB1)/AMP-dependent protein kinase (AMPK)/target of rapamycin complex (TORC) 1 was involved in regulation of NUCB-2-mediated metastasis and EMT properties. Suppression of NUCB-2 inhibited tumor nodules formation in a murine colon tumor model as well. In summary, nesfatin-1/NUCB-2 enhanced migration, invasion and EMT in colon cancer cells through LKB1/AMPK/TORC1/ZEB1 pathways in vitro and in vivo.

SUBMITTER: Kan JY

PROVIDER: S-EPMC5058760 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Nesfatin-1/Nucleobindin-2 enhances cell migration, invasion, and epithelial-mesenchymal transition via LKB1/AMPK/TORC1/ZEB1 pathways in colon cancer.

Kan Jung-Yu JY Yen Meng-Chi MC Wang Jaw-Yuan JY Wu Deng-Chyang DC Chiu Yen-Jung YJ Ho Ya-Wen YW Kuo Po-Lin PL

Oncotarget 20160501 21

Recent studies indicate that a high level of nesfatin-1/Nucleobindin-2 (NUCB-2) is associated with poor outcome and promotes cell migration in breast cancer and prostate cancer. However, the role of NUCB2 is not well known in colon cancer. In this study, NUCB-2 level in colon cancer tissue was higher than that in non-tumor tissue. Suppression of NUCB-2 in a colon cancer cell line SW620 inhibited migration and invasion. The microarray analysis showed that low expression level of transcription fac ...[more]

PMID: 27150059

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Project description:Nesfatin/Nucleobindin-2 (Nesf/NUCB2), a precursor of nesfatin-1, an anorexigenic protein, is ubiquitously expressed in peripheral tissues in addition to the hypothalamus. However, the role of intracellular Nesf/NUCB2 has not been established in the periphery.Nesf/NUCB2-transgenic (Tg) mice were generated, and chronological changes of body weight and daily food intake were measured in Nesf/NUCB2-Tg mice fed normal laboratory chow or 45% high-fat diet (HFD). In addition, changes of metabolic markers were evaluated in those mice.No differences were observed in daily food intake and body weight between Nesf/NUCB2-Tg mice (n=11) and their non-Tg littermates (n=11) fed normal chow. Nesf/NUCB2-Tg mice showed increased mRNA expression of oxytocin and corticotropin-releasing hormone and decreased mRNA expression of cocaine- and amphetamine-related transcript in the hypothalamus. Nesf/NUCB2-Tg mice fed 45% HFD (n=6) showed significantly higher increase in body weight than their non-Tg littermates fed the same diet (n=8); however, no difference was observed in daily food intake between these two groups. Further, Nesf/NUCB2-Tg mice fed 45% HFD showed a significant increase in the weight of the liver, subcutaneous fat, and brown adipose tissue and decrease in the expression of uncoupling protein-1 in the subcutaneous fat. Blood glucose levels of Nesf/NUCB2-Tg mice fed 45% HFD were not different from those of their non-Tg littermates fed the same diet. Insulin levels of these Tg mice were significantly higher than those of their non-Tg littermates. Histological analysis showed marked fat deposition in the hepatocytes surrounding the hepatic central veins in Nesf/NUCB2-Tg mice fed 45% HFD.Overexpression of Nesf/NUCB2 did not change food intake, but increased body weight only in Nesf/NUCB2-Tg mice fed HFD. The results of this study indicate that Nesf/NUCB2 was involved in the development of insulin resistance and fat deposition in the liver, independent of the modulation of energy intake.

Project description:BackgroundNucleobindin-2 (Nucb2) is a multidomain protein that, due to its structure, participates in many physiological processes. It was originally identified in several regions of the hypothalamus. However, more recent studies have redefined and extended the function of Nucb2 far beyond its initially observed role as a negative modulator of food intake.ResultsPreviously, we described Nucb2 as structurally divided into two parts: the Zn2+-sensitive N-terminal half and the Ca2+-sensitive C-terminal half. Here, we investigated the structural and biochemical properties of its C-terminal half, which, after posttranslational processing, yields the formation of a fully uncharacterized peptide product known as nesfatin-3. Nesfatin-3 likely contains all the key respective structural regions of Nucb2. Hence, we expected that its molecular properties and affinity toward divalent metal ions might resemble those of Nucb2. Surprisingly, the obtained results showed that the molecular properties of nesftain-3 were completely different from those of its precursor protein. Moreover, we designed our work as a comparative analysis of two nesfatin-3 homologs. We noticed that in their apo forms, both proteins had similar shapes and existed in solution as extended molecules. They both interacted with divalent metal ions, and this interaction manifested itself in a compaction of the protein molecules. Despite their similarities, the differences between the homologous nesfatin-3s were even more informative. Each of them favored interaction with a different metal cation and displayed unique binding affinities compared either to each other or to Nucb2.ConclusionsThe observed alterations suggested different from Nucb2 physiological roles of nesfatin-3 and different impacts on the functioning of the tissues and on metabolism and its control. Our results clearly demonstrated that nesfatin-3 possessed divalent metal ion binding properties, which remained hidden in the nucleobindin-2 precursor protein.

Dataset Information

Nesfatin-1/Nucleobindin-2 enhances cell migration, invasion, and epithelial-mesenchymal transition via LKB1/AMPK/TORC1/ZEB1 pathways in colon cancer.

Publications

Nesfatin-1/Nucleobindin-2 enhances cell migration, invasion, and epithelial-mesenchymal transition via LKB1/AMPK/TORC1/ZEB1 pathways in colon cancer.

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