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

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.

[1]  Hui Hu,et al.  AnimalTFDB 3.0: a comprehensive resource for annotation and prediction of animal transcription factors , 2018, Nucleic Acids Res..

[2]  H. Cui,et al.  Cancer-testis specific gene OIP5: a downstream gene of E2F1 that promotes tumorigenesis and metastasis in glioblastoma by stabilizing E2F1 signaling , 2018, Neuro-oncology.

[3]  Hui Zhang,et al.  MicroRNA-599 inhibits metastasis and epithelial-mesenchymal transition via targeting EIF5A2 in gastric cancer. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[4]  David J. Arenillas,et al.  JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web framework , 2017, Nucleic acids research.

[5]  David J. Arenillas,et al.  JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web framework , 2017, Nucleic acids research.

[6]  S. Friedman,et al.  Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. , 2017, Journal of hepatology.

[7]  Sung-Hoon Kim,et al.  Role of Forkhead Box Class O proteins in cancer progression and metastasis. , 2017, Seminars in cancer biology.

[8]  A. Jemal,et al.  Cancer statistics, 2018 , 2018, CA: a cancer journal for clinicians.

[9]  R. Luo,et al.  FOXA1 inhibits hepatocellular carcinoma progression by suppressing PIK3R1 expression in male patients , 2017, Journal of experimental & clinical cancer research : CR.

[10]  Lewis C. Cantley,et al.  The PI3K Pathway in Human Disease , 2017, Cell.

[11]  Yonghui Wang,et al.  Hsa-miR-599 suppresses the migration and invasion by targeting BRD4 in breast cancer , 2017, Oncology letters.

[12]  Xiangliang Zhang,et al.  Elevated FOXO6 expression correlates with progression and prognosis in gastric cancer , 2017, Oncotarget.

[13]  S. Banskota,et al.  Tryptophan hydroxylase 1 and 5-HT7 receptor preferentially expressed in triple-negative breast cancer promote cancer progression through autocrine serotonin signaling , 2016, Molecular Cancer.

[14]  S. Xiao,et al.  miRNA-487a Promotes Proliferation and Metastasis in Hepatocellular Carcinoma , 2016, Clinical Cancer Research.

[15]  B. Beutler,et al.  Insulin resistance and diabetes caused by genetic or diet-induced KBTBD2 deficiency in mice , 2016, Proceedings of the National Academy of Sciences.

[16]  A. Wahid,et al.  Serum serotonin as unexpected potential marker for staging of experimental hepatocellular carcinoma. , 2016, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[17]  Jingjing Tian,et al.  Identification a novel tumor-suppressive hsa-miR-599 regulates cells proliferation, migration and invasion by targeting oncogenic MYC in hepatocellular carcinoma. , 2016, American journal of translational research.

[18]  Jing-Song Chen,et al.  MicroRNA-379-5p inhibits tumor invasion and metastasis by targeting FAK/AKT signaling in hepatocellular carcinoma. , 2016, Cancer letters.

[19]  Shu-sen Zheng,et al.  Expression of FOXO6 is Associated With Oxidative Stress Level and Predicts the Prognosis in Hepatocellular Cancer , 2016, Medicine.

[20]  A. Tawfik,et al.  Could serotonin be a potential marker for hepatocellular carcinoma? A prospective single-center observational study , 2016, European journal of gastroenterology & hepatology.

[21]  Ge Zhang,et al.  5‐Hydroxytryptamine promotes hepatocellular carcinoma proliferation by influencing β‐catenin , 2016, Molecular oncology.

[22]  Zhe-Sheng Chen,et al.  5-hydroxytryptamine receptor (5-HT1DR) promotes colorectal cancer metastasis by regulating Axin1/β-catenin/MMP-7 signaling pathway , 2015, Oncotarget.

[23]  A. Jemal,et al.  Global cancer statistics, 2012 , 2015, CA: a cancer journal for clinicians.

[24]  M. Rivera,et al.  Inhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6-dependent survival pathways , 2015, eLife.

[25]  J. Hou,et al.  MicroRNA‐486‐5p, which is downregulated in hepatocellular carcinoma, suppresses tumor growth by targeting PIK3R1 , 2015, The FEBS journal.

[26]  J. Clarhaut,et al.  Serotonin and cancer: what is the link? , 2015, Current molecular medicine.

[27]  B. Ozpolat,et al.  Down-Regulation of 5-HT1B and 5-HT1D Receptors Inhibits Proliferation, Clonogenicity and Invasion of Human Pancreatic Cancer Cells , 2014, PloS one.

[28]  Wenxin Qin,et al.  Monoamine oxidase A suppresses hepatocellular carcinoma metastasis by inhibiting the adrenergic system and its transactivation of EGFR signaling. , 2014, Journal of hepatology.

[29]  K. Nakao,et al.  Antitumor function of microRNA-122 against hepatocellular carcinoma , 2014, Journal of Gastroenterology.

[30]  S. Brookes,et al.  Identification of unique release kinetics of serotonin from guinea‐pig and human enterochromaffin cells , 2013, The Journal of physiology.

[31]  Qi Zhang,et al.  Serotonin promotes the proliferation of serum-deprived hepatocellular carcinoma cells via upregulation of FOXO3a , 2013, Molecular Cancer.

[32]  M. Gershon.  5-Hydroxytryptamine (serotonin) in the gastrointestinal tract , 2013, Current opinion in endocrinology, diabetes, and obesity.

[33]  C. Hellerbrand,et al.  Expression of Serotonin Receptors in Human Hepatocellular Cancer , 2012, Clinical Cancer Research.

[34]  Aliyeh Zamani,et al.  Serotonin activates angiogenic phosphorylation signaling in human endothelial cells , 2012, FEBS letters.

[35]  N. Kato,et al.  MicroRNA122 is a key regulator of α-fetoprotein expression and influences the aggressiveness of hepatocellular carcinoma. , 2011, Nature communications.

[36]  H. Weiss,et al.  The effect of PTEN on serotonin synthesis and secretion from the carcinoid cell line BON. , 2011, Anticancer research.

[37]  W. Jochum,et al.  Serotonin reverts age-related capillarization and failure of regeneration in the liver through a VEGF-dependent pathway , 2011, Proceedings of the National Academy of Sciences.

[38]  R. Poulsom,et al.  CUX1: target of Akt signalling and mediator of resistance to apoptosis in pancreatic cancer , 2010, Gut.

[39]  P. Wild,et al.  Serotonin promotes tumor growth in human hepatocellular cancer , 2010, Hepatology.

[40]  B. Liu,et al.  Smad6 Inhibits the Transcriptional Activity of Tbx6 by Mediating Its Degradation* , 2009, The Journal of Biological Chemistry.

[41]  A. Franchitto,et al.  Serotonin metabolism is dysregulated in cholangiocarcinoma, which has implications for tumor growth. , 2008, Cancer research.

[42]  D. Mann,et al.  The function of serotonin within the liver. , 2008, Journal of hepatology.

[43]  J. Tack,et al.  REVIEWS IN BASIC AND CLINICAL GASTROENTEROLOGY The Serotonin Signaling System: From Basic Understanding To Drug Development for Functional GI Disorders , 2007 .

[44]  D. Ganea,et al.  A Novel Signaling Pathway Mediates the Inhibition of CCL3/4 Expression by Prostaglandin E2* , 2004, Journal of Biological Chemistry.

[45]  P. Wijchers,et al.  FoxO6, a Novel Member of the FoxO Class of Transcription Factors with Distinct Shuttling Dynamics* , 2003, Journal of Biological Chemistry.

[46]  Xavier Messeguer,et al.  PROMO: detection of known transcription regulatory elements using species-tailored searches , 2002, Bioinform..

[47]  D. Skalnik,et al.  CCAAT Displacement Protein (CDP/Cut) Binds a Negative Regulatory Element in the Human Tryptophan Hydroxylase Gene , 1999, Journal of neurochemistry.

[48]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.