{
  "abstract": "Background Our previous genome-wide association study (GWAS) identified that chromosome 1p36.22 locus contributes to the risk of hepatocellular carcinoma (HCC).Objective We aimed to identify the functional causative variant(s) and target gene(s) at this locus.Design Two independent HCC case–control populations, totally consisting of 1934 cases and 1446 controls, were used to validate the association between 1p36.22 locus and HCC risk. The expression quantitative trait locus (eQTL) and eQTL-GWAS co-localisation analyses were used to identify the target gene at 1p36.22. The effects of the target gene on tumourigenesis were assessed in HCC cells, nude mouse models and conditional knockout mouse models.Results We confirmed the association between 1p36.22 locus and HCC risk (p=4.99×10 −24), and revealed that this locus is an eQTL of the kinesin family member 1B isoform β (KIF1Bβ) gene. Further, we demonstrated that KIF1Bβ plays a tumour suppressive role in HCC in vitro and in vivo. Mechanistically, KIF1Bβ interacts with the cargo Fibulin-5 and mediates its intracellular anterograde transport and extracellular secretion, therefore, reducing the activation of the integrin pathway. We further identified the functional causative variant rs61784580 at 1p36.22, which is located in the promoter of KIF1Bβ and regulates its expression in an allele-specific manner. Finally, we observed that downregulation of KIF1Bβ sensitises HCC cells to integrin αv inhibitor cilengitide.Conclusions Our findings shed light on the genetic and molecular mechanisms of the HCC-associated susceptibility locus at 1p36.22 and provide potential new strategies for the treatment of HCC.",
  "authors": [
    {
      "affiliations": [
        "State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, Beijing, China"
      ],
      "name": "Chengming Gao"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, Beijing, China",
        "Department of Gastroenterology, National Clinical Research Center for Digestive Diseases, Changhai Hospital, Naval Medical University, Shanghai, China"
      ],
      "name": "Yahui Wang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, Beijing, China"
      ],
      "name": "Guangming Zhou"
    },
    {
      "affiliations": [
        "College of Life Sciences, Hebei University College of Life Sciences, Baoding, Hebei, China"
      ],
      "name": "Peipei Shi"
    },
    {
      "affiliations": [
        "College of Life Sciences, Hebei University College of Life Sciences, Baoding, Hebei, China"
      ],
      "name": "Ji-Ao Wang"
    },
    {
      "affiliations": [
        "College of Life Sciences, Anhui Medical University, Hefei, Anhui, China"
      ],
      "name": "Junjie Wu"
    },
    {
      "affiliations": [
        "Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China"
      ],
      "name": "Song Liao"
    },
    {
      "affiliations": [
        "College of Life Sciences, Hebei University College of Life Sciences, Baoding, Hebei, China"
      ],
      "name": "Han Yan"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, Beijing, China"
      ],
      "name": "Yifei Qiu"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, Beijing, China"
      ],
      "name": "Hongbo Yan"
    },
    {
      "affiliations": [
        "Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China"
      ],
      "name": "Tao Zeng"
    },
    {
      "affiliations": [
        "Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China"
      ],
      "name": "Ruofan Li"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, Beijing, China"
      ],
      "name": "Ying Zhang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, Beijing, China"
      ],
      "name": "Pengbo Cao"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, Beijing, China"
      ],
      "name": "Chenning Yang"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary & Pancreatic Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China"
      ],
      "name": "Jiazhou Ye"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary & Pancreatic Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China"
      ],
      "name": "Rong Liang"
    },
    {
      "affiliations": [
        "College of Chemistry & Materials Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis, Hebei University, Baoding, Hebei, China"
      ],
      "name": "Yuting Wang"
    },
    {
      "affiliations": [
        "College of Life Sciences, Hebei University College of Life Sciences, Baoding, Hebei, China"
      ],
      "name": "Furong Cheng"
    },
    {
      "affiliations": [
        "College of Life Sciences, Hebei University College of Life Sciences, Baoding, Hebei, China"
      ],
      "name": "Kaina Hao"
    },
    {
      "affiliations": [
        "College of Life Sciences, Hebei University College of Life Sciences, Baoding, Hebei, China"
      ],
      "name": "Jinwen Zhang"
    },
    {
      "affiliations": [
        "College of Life Sciences, Hebei University College of Life Sciences, Baoding, Hebei, China"
      ],
      "name": "Xiaoyu Hu"
    },
    {
      "affiliations": [
        "College of Life Sciences, Hebei University College of Life Sciences, Baoding, Hebei, China"
      ],
      "name": "Rui Guo"
    },
    {
      "affiliations": [
        "College of Life Sciences, Hebei University College of Life Sciences, Baoding, Hebei, China"
      ],
      "name": "Qiming Wang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China"
      ],
      "name": "Fuchu He"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, Beijing, China",
        "College of Chemistry & Materials Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis, Hebei University, Baoding, Hebei, China"
      ],
      "name": "Yuanfeng Li"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, Beijing, China",
        "College of Life Sciences, Hebei University College of Life Sciences, Baoding, Hebei, China",
        "College of Life Sciences, Anhui Medical University, Hefei, Anhui, China",
        "Collaborative Innovation Center for Personalized Cancer Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China"
      ],
      "name": "Gangqiao Zhou"
    }
  ],
  "title": "KIF1Bβ suppresses hepatocellular carcinoma by transporting and secreting FBLN5 to attenuate the integrin pathway",
  "uid": "ea565ee0-9344-549b-8997-20e7d4318aa9"
}