title: Histidine-rich calcium binding protein promotes growth of hepatocellular carcinoma in vitro and in vivo.
abstract: We have recently shown that the histidine-rich calcium binding protein (HRC) promotes the invasion and metastasis of hepatocellular carcinoma (HCC). In the current study, we evaluated whether HRC may also affect the growth of HCC. We found that ectopic expression of HRC obviously enhanced proliferation and colony formation, while suppression of HRC exhibited inhibitory effects. Furthermore, we demonstrated that HRC promoted tumor growth in nude mice. These effects may result from the ability of HRC to upregulate cyclinD1 and cyclin-dependent kinase 2 (CDK2) expressions and promote G1/S transition. Further study showed that MEK/ERK signaling pathway was involved in HRC-induced cell proliferation. Interestingly, overexpression or depletion of HRC revealed its regulation on endoplasmic reticulum stress (ERS) and apoptosis, which was partially dependent on PERK/ATF4/CHOP signaling pathway. In addition, blocking ERS using 4-phenylbutyric acid (4-PBA) not only downregulated the expression of PERK, ATF4 and CHOP, but also significantly decreased apoptosis induced by HRC silence, whereas ERS inducer thapsigargin (TG) exerted the opposite effects. Our study thus demonstrates a role of HRC in promoting HCC growth, besides its role in inducing HCC metastasis, and highlights HRC as a promising intervention target for HCC.
authors.affiliation: Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jingmei
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Han
authors.affiliation: Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Mengke
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.affiliation: Department of Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jiqiao
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jiayi
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Gong
authors.affiliation: Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yunwu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Dean
authors.initials: D
authors.lastname: Tian
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010654:Phenylbutyrates / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D019284:Thapsigargin / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000378:metabolism; D014183:Transplantation, Heterologous; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: C497109:ATF4 protein, human; D002135:Calcium-Binding Proteins; C497249:DDIT3 protein, human; D010654:Phenylbutyrates; D034741:RNA, Small Interfering; C068969:HRC protein, human; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D019284:Thapsigargin; C075773:4-phenylbutyric acid; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase; D053148:Caspase 3
keywords: Apoptosis; endoplasmic reticulum stress; hepatocellular carcinoma; histidine-rich calcium binding protein; proliferation