Serotonin and YAP/VGLL4 Balance Correlated with Progression and Poor Prognosis of Hepatocellular Carcinoma

Shu, Bo; Zhai, Mimi; Miao, Xiangshui; He, Chao; Deng, Chaolin; Yu, Fang; Luo, Mi; Liu, Luyao; Liu, Sushun

doi:10.1038/s41598-018-28075-9

Cited by 18 publications

(18 citation statements)

References 27 publications

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“…VGLL4 expression is reduced and has been verified as a tumour suppressor in HCC. 35 Adenovirus-mediated VGLL4 suppresses cell proliferation, causes G2/M phase arrest and enhances apoptosis of HCC cells, and restrains tumour growth of HCC in vivo. 36 In this study, miR-301b-3p F I G U R E 4 Vestigial like family member 4 (VGLL4) is identified as a novel target of miR-301b-3p.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‐301b‐3p contributes to tumour growth of human hepatocellular carcinoma by repressing vestigial like family member 4

Guo

Yao

Zhu

et al. 2019

J Cellular Molecular Medi

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Micro RNA s (mi RNA s) are key regulators in the tumour growth and metastasis of human hepatocellular carcinoma ( HCC ). Increasing evidence suggests that miR‐301b‐3p functions as a driver in various types of human cancer. However, the expression pattern of miR‐301b‐3p and its functional role as well as underlying molecular mechanism in HCC remain poorly known. Our study found that miR‐301b‐3p expression was significantly up‐regulated in HCC tissues compared to adjacent non‐tumour tissues. Clinical association analysis revealed that the high level of miR‐301b‐3p closely correlated with large tumour size and advanced tumour‐node‐metastasis stages. Importantly, the high miR‐301b‐3p level predicted a prominent poorer overall survival of HCC patients. Knockdown of miR‐301b‐3p suppressed cell proliferation, led to cell cycle arrest at G2/M phase and induced apoptosis of Huh7 and Hep3B cells. Furthermore, miR‐301b‐3p knockdown suppressed tumour growth of HCC in mice. Mechanistically, miR‐301b‐3p directly bond to 3′ UTR of vestigial like family member 4 ( VGLL 4) and negatively regulated its expression. The expression of VGLL 4 mRNA was down‐regulated and inversely correlated with miR‐301b‐3p level in HCC tissues. Notably, VGLL 4 knockdown markedly repressed cell proliferation, resulted in G2/M phase arrest and promoted apoptosis of HCC cells. Accordingly, VGLL 4 silencing rescued miR‐301b‐3p knockdown attenuated HCC cell proliferation, cell cycle progression and apoptosis resistance. Collectively, our results suggest that miR‐301b‐3p is highly expressed in HCC . miR‐301b‐3p facilitates cell proliferation, promotes cell cycle progression and inhibits apoptosis of HCC cells by repressing VGLL 4.

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Section: Discussionmentioning

confidence: 99%

MicroRNA‐301b‐3p contributes to tumour growth of human hepatocellular carcinoma by repressing vestigial like family member 4

Guo

Yao

Zhu

et al. 2019

J Cellular Molecular Medi

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“…Several studies have demonstrated that peripheral serotonin is also involved in liver cancer progression. Increased serum and plasma serotonin levels were found in HCC patients [ 45 ]. Serum serotonin levels are also higher in cirrhotic patients compared with chronic hepatitis, and cirrhotic patients with HCC compared with and cirrhotic patients without HCC [ 46 ].…”

Section: Discussionmentioning

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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“…An increasing number of studies have highlighted the association of YAP/TAZ expression in tumor cells with tumor prognosis and therapeutic responses, but the role of YAP/TAZ in tumor immunity is less well characterized (131)(132)(133)(134)(135). The TME encompasses tumor cells, immune cells, and other cell types.…”

Section: The Role Of Yap/taz Signaling Of Tumor Immunity In Tumor Promentioning

confidence: 99%

The Emerging Role of YAP/TAZ in Tumor Immunity

Pan

Tian²,

Cao

et al. 2019

Molecular Cancer Research

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Yes-associated protein (YAP)/WW domain-containing transcription regulator 1 (TAZ) is an important transcriptional regulator and effector of the Hippo signaling pathway that has emerged as a critical determinant of malignancy in many human tumors. YAP/TAZ expression regulates the cross-talk between immune cells and tumor cells in the tumor microenvironment through its influence on T cells, myeloid-derived suppressor cells, and macrophages. However, the mechanisms underlying these effects are poorly understood. An improved understanding of the role of YAP/TAZ in tumor immunity is essential for exploring innovative tumor treatments and making further breakthroughs in antitumor immunotherapy. This review primarily focuses on the role of YAP/TAZ in immune cells, their interactions with tumor cells, and how this impacts on tumorigenesis, progression, and therapy resistance.

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Serotonin and YAP/VGLL4 Balance Correlated with Progression and Poor Prognosis of Hepatocellular Carcinoma

Cited by 18 publications

References 27 publications

MicroRNA‐301b‐3p contributes to tumour growth of human hepatocellular carcinoma by repressing vestigial like family member 4

MicroRNA‐301b‐3p contributes to tumour growth of human hepatocellular carcinoma by repressing vestigial like family member 4

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

The Emerging Role of YAP/TAZ in Tumor Immunity

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