title: The histidine-rich calcium binding protein (HRC) promotes tumor metastasis in hepatocellular carcinoma and is upregulated by SATB1.
abstract: The histidine-rich calcium binding protein (HRC) is a regulator of Ca2+-homeostasis. Herein, we found that HRC was frequently upregulated in human hepatocellular carcinoma (HCC) tissues, and its expression was correlated with tumor size and metastasis. Moreover, HRC expression was positively related to the metastatic potential of HCC cell lines. Knockdown of HRC suppressed cell invasion and migration in vitro, whereas ectopic expression of HRC resulted in increased cell invasion and migration in vitro and intrahepatic and lung metastasis in vivo. Interestingly, the pro-invasion and pro-migration effects of HRC were associated with focal adhesion turnover, which was a consequence of FAK phosphorylation. Further experiments showed that HRC induced phospho-FAK, focal adhesion turnover and cell migration through Ca2+/CaM singaling. We found that HRC increased [Ca2+]i by inhibiting the expression of SERCA2. In addition, upregulation of HRC in HCC was attributed to SATB1, which is known to promote HCC metastasis. Ectopic expression of SATB1 enhanced HRC gene transcription by activating AP-1 in mainly a JNK-dependent manner. Our findings highlight HRC as a potential therapeutic target for HCC treatment.
authors.affiliation: Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Jingmei
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Han
authors.affiliation: Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Mengke
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.affiliation: Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Medical Ultrasound, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Jiqiao
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Jiayi
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Tu
authors.affiliation: Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Yujia
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Gong
authors.affiliation: Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ding
authors.affiliation: Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Dean
authors.initials: D
authors.lastname: Tian
mesh_terms: D000328:Adult; D000818:Animals; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D008297:Male; D036961:Matrix Attachment Region Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D034622:RNA Interference; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation
chemical_list: D002135:Calcium-Binding Proteins; D002147:Calmodulin; D036961:Matrix Attachment Region Binding Proteins; C076189:SATB1 protein, human; D018808:Transcription Factor AP-1; C068969:HRC protein, human; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human
keywords: HRC; SATB1; focal adhesion turnover; hepatocellular carcinoma; metastasis