Serotonin and the 5‐<scp>HT</scp>7 receptor: The link between hepatocytes, <scp>IGF</scp>‐1 and small intestinal neuroendocrine tumors

Svejda, Bernhard; Kidd, Mark; Timberlake, Andrew T.; Harry, Kathy; Kazberouk, Alexander; Schimmack, Simon; Lawrence, Ben; Pfragner, Roswitha; Modlin, Irvin M.

doi:10.1111/cas.12174

Cited by 35 publications

(24 citation statements)

References 72 publications

(143 reference statements)

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“…Target genes encompassed by these GO terms for both miRNAs included those normally upregulated in oncogenesis, such as NUAK2 (Namiki et al 2011), EGFR (copy number gain seen in 4% SBNETs (Banck et al 2013)), KRAS, NRAS, IGF1 , Reidy-Lagunes et al 2012, MAPK1 (ERK1) , BCL2, ARHGEF7 and BMP7 (Supplementary Table 4). Target genes specific only for miR-1 included HGF (Svejda et al 2013) and VEGFA. These data suggest that downregulation of these two miRNAs could be key in the development of SBNET metastases through reduced repression of these genes and increased cancer cell survival.…”

Section: :9 Micrornas Appear Deregulated In Liver Metastases From Smentioning

confidence: 99%

MicroRNAs associated with small bowel neuroendocrine tumours and their metastases

Miller¹,

Frampton²,

Malczewska³

et al. 2016

Endocrine-Related Cancer

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Novel molecular analytes are needed in small bowel neuroendocrine tumours (SBNETs) to better determine disease aggressiveness and predict treatment response. In this study, we aimed to profile the global miRNome of SBNETs, and identify microRNAs (miRNAs) involved in tumour progression for use as potential biomarkers. Two independent miRNA profiling experiments were performed (n = 90), including primary SBNETs (n = 28), adjacent normal small bowel (NSB; n = 14), matched lymph node (LN) metastases (n = 24), normal LNs (n = 7), normal liver (n = 2) and liver metastases (n = 15). We then evaluated potentially targeted genes by performing integrated computational analyses. We discovered 39 miRNAs significantly deregulated in SBNETs compared with adjacent NSB. The most upregulated (miR-204-5p, miR-7-5p and miR-375) were confirmed by qRT-PCR. Two miRNAs (miR-1 and miR-143-3p) were significantly downregulated in LN and liver metastases compared with primary tumours. Furthermore, we identified upregulated gene targets for miR-1 and miR-143-3p in an existing SBNET dataset, which could contribute to disease progression, and show that these miRNAs directly regulate FOSB and NUAK2 oncogenes. Our study represents the largest global miRNA profiling of SBNETs using matched primary tumour and metastatic samples. We revealed novel miRNAs deregulated during SBNET disease progression, and important miRNA-mRNA interactions. These miRNAs have the potential to act as biomarkers for patient stratification and may also be able to guide treatment decisions. Further experiments to define molecular mechanisms and validate these miRNAs in larger tissue cohorts and in biofluids are now warranted.

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Section: :9 Micrornas Appear Deregulated In Liver Metastases From Smentioning

confidence: 99%

MicroRNAs associated with small bowel neuroendocrine tumours and their metastases

Miller¹,

Frampton²,

Malczewska³

et al. 2016

Endocrine-Related Cancer

Self Cite

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“…15 When small intestinal (SI) neuroendocrine neoplasms (NENs) metastasize to the liver, hepatocytes respond to elevated 5-HT levels produced by specific SI NENs with increased secretion of IGF-1 via the 5-HT 7 receptor/Akt pathway, and the paracrine production of IGF-1, in turn, supports tumor cell proliferation. 16 In triple-negative breast cancer (TNBC), the autocrine effects of 5-HT on MDA-MB-231 cell proliferation and invasion were mediated through the 5-HT 7 receptor. 17,18 A B C D E Considering the markedly high expression of 5-HT 7 receptors in the lung tissues of NSCLC patients, the 5-HT 7 receptor functional significance in GO term enrichment and KEGG pathway enrichment analyses of the DEGs, and the lack of investigation of 5-HT 7 receptors in NSCLC, we carried out this study.…”

Section: Discussionmentioning

confidence: 99%

“…10 In addition to its wellestablished role in cognition, 11 circadian rhythms 12 and depression, 13 its involvement in various cancers has also been reported. [14][15][16][17][18] Although the 5-HT 7 receptor has been implicated in many lung-associated pathologic processes in rats 19,20 and guinea-pigs, 21,22 research on the 5-HT 7 receptor in human lungs is limited. 23 In our study, an exploration of mRNA expression using bioinformatics analysis and the results of immunohistochemistry analysis both showed higher 5-HT 7 receptor expression levels in the tumor tissues of NSCLC than in adjacent normal tissues, which indicates that the 5-HT 7 receptor may play a role in the progression of NSCLC.…”

Section: Introductionmentioning

confidence: 99%

<p>5-HT<sub>7</sub> Receptor Contributes to Proliferation, Migration and Invasion in NSCLC Cells</p>

Du¹,

Wang²,

Wang³

et al. 2020

OTT

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Introduction: Because only a small portion of NSCLC (non-small-cell lung cancer) patients benefit from molecular targeted therapy or immunotherapy and do not develop therapeutic resistance, continued research on new targets is warranted. Serotonin has recently emerged as a growth factor for tumor cells, and its receptors may be potential therapeutic targets. The mechanism related to the behavior of the 5-HT 7 receptor in NSCLC remains unknown. Methods: Both gene expression analysis and immunohistochemical analysis were conducted to evaluate 5-HT 7 receptor expression in NSCLC tissues. The correlation between 5-HT 7 receptor expression and clinicopathological features was also examined. Cell proliferation was measured using a CCK8 (Cell Counting Kit-8) assay and colony formation, migration and invasion were evaluated by the Transwell assay. siRNA transfection and stimulation with the selective agonist LP211 were used to identify the involvement of molecules in proliferation, migration and invasion. Quantitative real-time chain reaction (qRT-PCR) and Western blotting were used to quantifiy mRNA and protein levels, respectively. Pathway inhibitors facilitated the exploration of possible signaling pathways regulated by the 5-HT 7 receptor in migration and invasion. Results: The 5-HT 7 receptor was overexpressed in NSCLC tumor tissues compared with adjacent normal lung tissues. High 5-HT 7 receptor expression levels were correlated with lymph node metastasis (P=0.007) and advanced TNM stage (P=0.000) in NSCLC patients. The 5-HT 7 receptor positively regulated cell proliferation, migration and invasion in NSCLC cells. The stimulatory effect of the 5-HT 7 receptor on A549 cell migration and invasion may occur through the P38 pathway. In H1299 cells, the 5-HT 7 receptor might positively regulate Src to promote cell migration and invasion. Conclusion: Our findings suggest that the 5-HT 7 receptor, which mediates NSCLC progression, may be a potential therapeutic target.

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“…Serotonin, a monoamine synthesized by enterochromaffin cells in the intestinal mucosa, is largely (about 95%) sequestered by platelets in dense granules, from which it is released in response to various stimuli [12]. A large body of experimental data support both stimulatory and inhibitory properties of serotonin on tumor onset and progression [129][130][131][132][133][134]. Such different behavior is much likely due to the ability of serotonin to act in a concentration-dependent manner, as well as in its capability to activate distinct signaling pathways, depending on the receptor subtype present at various tumor stages.…”

Section: Platelet-derived Bioactive Compoundsmentioning

confidence: 99%

The “Janus Face” of Platelets in Cancer

Catani

Savini

Tullio

et al. 2020

IJMS

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Besides their vital role in hemostasis and thrombosis, platelets are also recognized to be involved in cancer, where they play an unexpected central role: They actively influence cancer cell behavior, but, on the other hand, platelet physiology and phenotype are impacted by tumor cells. The existence of this platelet-cancer loop is supported by a large number of experimental and human studies reporting an association between alterations in platelet number and functions and cancer, often in a way dependent on patient, cancer type and treatment. Herein, we shall report on an update on platelet-cancer relationships, with a particular emphasis on how platelets might exert either a protective or a deleterious action in all steps of cancer progression. To this end, we will describe the impact of (i) platelet count, (ii) bioactive molecules secreted upon platelet activation, and (iii) microvesicle-derived miRNAs on cancer behavior. Potential explanations of conflicting results are also reported: Both intrinsic (heterogeneity in platelet-derived bioactive molecules with either inhibitory or stimulatory properties; features of cancer cell types, such as aggressiveness and/or tumour stage) and extrinsic (heterogeneous characteristics of cancer patients, study design and sample preparation) factors, together with other confounding elements, contribute to “the Janus face” of platelets in cancer. Given the difficulty to establish the univocal role of platelets in a tumor, a better understanding of their exact contribution is warranted, in order to identify an efficient therapeutic strategy for cancer management, as well as for better prevention, screening and risk assessment protocols.

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Serotonin and the 5‐HT7 receptor: The link between hepatocytes, IGF‐1 and small intestinal neuroendocrine tumors

Cited by 35 publications

References 72 publications

MicroRNAs associated with small bowel neuroendocrine tumours and their metastases

MicroRNAs associated with small bowel neuroendocrine tumours and their metastases

<p>5-HT<sub>7</sub> Receptor Contributes to Proliferation, Migration and Invasion in NSCLC Cells</p>

The “Janus Face” of Platelets in Cancer

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