5‐Hydroxytryptamine promotes hepatocellular carcinoma proliferation by influencing β‐catenin

Fatima, Sarwat; Shi, Xiaoke; Lin, Zesi; Chen, Guo Qing; Pan, Xiaohua; Wu, Justin C. Y.; Ho, John W.; Lee, Nikki P.; Gao, Hengjun; Zhang, Ge; Lu, Aiping; Bian, Zhao Xiang

doi:10.1016/j.molonc.2015.09.008

Cited by 58 publications

(45 citation statements)

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“…5-HTr3 is the only ligand-gated ion channel serotonin receptor, whereas, all other serotonin receptors belong to the G-protein coupled receptor superfamily [ 2 , 5 , 12 ]. Overexpression of 5-HTr1D, 5-HTr2B and 5-HTr7 and lower expression of 5-HTr2A and 5-HTr5 has been reported in hepatocellular carcinoma (HCC) compared with adjacent non-tumor tissue [ 13 ]. Tissue microarray and immunohistochemistry data generated from liver cancer patients suggested that expression of 5-HTr1B and 5-HTr2B are associated with cell proliferation index, and 5-HTr1B expression is correlated with the size of the liver tumor in patients [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Serotonin induced hepatic steatosis is associated with modulation of autophagy and notch signaling pathway

et al. 2018

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BackgroundBesides its neurotransmitter and vasoconstriction functions, serotonin is an important mediator of numerous biological processes in peripheral tissues including cell proliferation, steatosis, and fibrogenesis. Recent reports indicate that serotonin may promote tumor growth in liver cancer, however, the molecular mechanisms remain elusive. n this study, we investigated the role and molecular signaling mechanisms mediated by serotonin in liver cancer cell survival, drug resistance, and steatosis.MethodsEffect of serotonin on modulation of cell survival/proliferation was determined by MTT/WST1 assay. Effect of serotonin on the regulation of autophagy biomarkers and lipid/fatty acid proteins expression, AKT/mTOR and Notch signaling was evaluated by immunoblotting. The role of serotonin in normal human hepatocytes and liver cancer cell steatosis was analyzed by Oil Red O staining. The mRNA expression levels of lipid/fatty acid proteins and serotonin receptors were validated by qRT-PCR. The important roles of autophagy, Notch signaling, serotonin receptors and serotonin re-uptake proteins on serotonin-mediated cell steatosis were investigated by using selective inhibitors or antagonists. The association of peripheral serotonin, autophagy, and hepatic steatosis was also investigated using chronic EtOH fed mouse model.ResultsExposure of liver cancer cells to serotonin induced Notch signaling and autophagy, independent of AKT/mTOR pathway. Also, serotonin enhanced cancer cell proliferation/survival and drug resistance. Furthermore, serotonin treatment up-regulated the expression of lipogenic proteins and increased steatosis in liver cancer cells. Inhibition of autophagy or Notch signaling reduced serotonin-mediated cell steatosis. Treatment with serotonin receptor antagonists 5-HTr1B and 5-HTr2B reduced serotonin-mediated cell steatosis; in contrast, treatment with selective serotonin reuptake inhibitors (SSRIs) increased steatosis. In addition, mice fed with chronic EtOH resulted in increased serum serotonin levels which were associated with the induction of hepatic steatosis and autophagy.ConclusionsSerotonin regulates liver cancer cell steatosis, cells survival, and may promote liver carcinogenesis by activation of Notch signaling and autophagy.Electronic supplementary materialThe online version of this article (10.1186/s12964-018-0282-6) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Serotonin induced hepatic steatosis is associated with modulation of autophagy and notch signaling pathway

et al. 2018

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“…5‐HT is a potent mitogen for hepatocytes, and it is crucial for liver regeneration . Through activating the Wnt/β‐catenin signaling pathway, 5‐HT promotes HCC proliferation, migration, invasion, and angiogenesis through receptor 5‐HT7 . 5‐HT can be used to screen for early‐stage HCC and HCC in patients with cirrhosis with chronic hepatitis C infection …”

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confidence: 99%

5‐Hydroxytryptamine Receptor 1D Aggravates Hepatocellular Carcinoma Progression Through FoxO6 in AKT‐Dependent and Independent Manners

et al. 2019

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Serotonin and its receptors have been shown to play critical regulatory roles in cancer biology. Nevertheless, the contributions of 5‐hydroxytryptamine 1D (5‐HT1D), an indispensable member of the serotonergic system, to hepatocellular carcinoma (HCC) remain unknown. The present study demonstrated that the 5‐HT1D expression level was significantly up‐regulated in HCC tissues and cell lines. The 5‐HT1D expression level was closely correlated with unfavorable clinicopathological characteristics. Survival analyses show that elevated 5‐HT1D expression level predicts poor overall survival and high recurrence probability in HCC patients. Functional studies revealed that 5‐HT1D significantly promoted HCC proliferation, epithelial‐mesenchymal transition, and metastasis in vitro and in vivo. Mechanistically, 5‐HT1D could stabilize PIK3R1 by inhibiting its ubiquitin‐mediated degradation. The interaction between 5‐HT1D and phosphoinositide‐3‐kinase regulatory subunit 1 (PIK3R1) enhanced the expression of FoxO6 through the PI3K/Akt signaling pathway; FoxO6 could also be directly transcriptionally activated by 5‐HT1D in an Akt‐independent manner. MicroRNA‐599 was found to be an upstream suppressive modulator of 5‐HT1D. Additionally, 5‐HT1D could attenuate tryptophan hydroxylase 1 expression through the PI3K/Akt/cut‐like homeobox 1 axis in HCC. Conclusion: Herein, we uncovered the potent oncogenic effect of 5‐HT1D on HCC by interacting with PIK3R1 to activate the PI3K/Akt/FoxO6 pathway, and provided a potential therapeutic target for HCC.

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“…On the one hand, serotonin could stimulate liver regeneration after hepatectomy [34]. On the other hand, serotonin may aggravate the progress of nonalcoholic fatty liver, liver fibrosis, and hepatocellular carcinoma [22][23][24]. Figure 4: Serotonin exacerbated oxidative stress-mediated hepatocellular injury in Con A-mediated ALI mice.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that peripheral serotonin participates in platelet aggregation, gastrointestinal peristalsis, oxidative stress injury, inflammation and immune response, and so forth [15][16][17][18][19][20][21]. In addition, peripheral serotonin may be involved in the progress of several liver diseases such as liver regeneration, viral hepatitis, nonalcoholic steatohepatitis, hepatic fibrosis, and hepatocellular carcinoma via binding to 5-HT 2A and 2B receptors in liver tissue [22][23][24][25]. However, the role of peripheral serotonin in Con A-induced ALI remains unclear.…”

Section: Introductionmentioning

confidence: 99%

The Role of Serotonin in Concanavalin A-Induced Liver Injury in Mice

Pang

Jin

et al. 2020

Oxidative Medicine and Cellular Longevity

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Serotonin is involved in the pathological processes of several liver diseases via the regulation of inflammatory response and oxidative stress. We aimed to investigate the role of serotonin in Concanavalin A- (Con A-) induced acute liver injury (ALI). ALI was induced in C57B/6 wild-type (WT) mice and tryptophan hydroxylase 1 (TPH1) knockout mice through tail vein injection of Con A (15 mg/kg body weight). Another group of TPH1 knockout ALI mice was supplied with 5-hydroxytryptophan (5-HTP) in advance to recover serotonin. The blood and liver tissues of mice were collected in all groups. Markedly increased serum levels of serotonin were identified after the injection of Con A. Increased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and stronger hepatic tissue pathology were detected, suggesting that serotonin could mediate Con A-induced liver damage. Serotonin significantly facilitated the release of serum and intrahepatic inflammatory cytokines, including interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-17A (IL-17A), interferon-gamma (IFN-γ), and tumor necrosis-alpha (TNF-α), after the administration of Con A. In addition, serotonin significantly increased the intrahepatic levels of oxidative stress markers malonaldehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) and decreased antioxidant stress indicator glutathione (GSH) in Con A-treated mice. Additionally, serotonin promoted hepatocyte apoptosis and autophagy based on B-cell lymphoma-2 (Bcl-2), Bcl-2-asociated X protein (Bax), and Beclin-1 levels and TUNEL staining. More importantly, serotonin activated nuclear factor kappa B (NF-κB) and upregulated the hepatic expressions of high mobility group protein B1 (HMGB1), toll-like receptor-4 (TLR4), and downstream molecules in Con A-mediated liver injury. Serotonin 2A receptor was upregulated in liver tissue after Con A injection, and serotonin 2A receptor antagonist Ketanserin protected against Con A-induced hepatitis. These results indicated that serotonin has the potential to aggravate Con A-induced ALI via the promotion of inflammatory response, oxidative stress injury, and hepatocyte apoptosis and the activation of hepatic HMGB1-TLR signaling pathway and serotonin 2A receptor.

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5‐Hydroxytryptamine promotes hepatocellular carcinoma proliferation by influencing β‐catenin

Abstract: A B S T R A C T5-Hydroxytryptamine (5-HT), a neurotransmitter and vasoactive factor, has been reported to promote proliferation of serum-deprived hepatocellular carcinoma (HCC) cells but the detailed intracellular mechanism is unknown. As Wnt/b-catenin signalling is highly dysre-

Cited by 58 publications

References 47 publications

Serotonin induced hepatic steatosis is associated with modulation of autophagy and notch signaling pathway

Serotonin induced hepatic steatosis is associated with modulation of autophagy and notch signaling pathway

5‐Hydroxytryptamine Receptor 1D Aggravates Hepatocellular Carcinoma Progression Through FoxO6 in AKT‐Dependent and Independent Manners

The Role of Serotonin in Concanavalin A-Induced Liver Injury in Mice

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