The histidine-rich calcium binding protein (HRC) promotes tumor metastasis in hepatocellular carcinoma and is upregulated by SATB1

Jingmei Liu; Ping Han; Mengke Li; Wei Yan; Jin Liu; Jiqiao Liu; Jiayi He; Wei Tu; Yujia Xia; Zhenzhen Zhou; Jin Gong; Mei Liu; Qiang Ding; Dean Tian

doi:10.18632/oncotarget.3049

The histidine-rich calcium binding protein (HRC) promotes tumor metastasis in hepatocellular carcinoma and is upregulated by SATB1

Oncotarget. 2015 Mar 30;6(9):6811-24. doi: 10.18632/oncotarget.3049.

Authors

Jingmei Liu¹, Ping Han¹, Mengke Li¹, Wei Yan¹, Jin Liu¹, Jiqiao Liu², Jiayi He¹, Wei Tu¹, Yujia Xia¹, Zhenzhen Zhou¹, Jin Gong¹, Mei Liu¹, Qiang Ding¹, Dean Tian¹

Affiliations

¹ Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
² Department of Medical Ultrasound, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.

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.

Keywords: HRC; SATB1; focal adhesion turnover; hepatocellular carcinoma; metastasis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
Calcium Signaling
Calcium-Binding Proteins / genetics
Calcium-Binding Proteins / metabolism*
Calmodulin / metabolism
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / metabolism*
Carcinoma, Hepatocellular / secondary
Cell Line, Tumor
Cell Movement*
Female
Focal Adhesion Kinase 1 / metabolism
Focal Adhesions / metabolism
Focal Adhesions / pathology
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
JNK Mitogen-Activated Protein Kinases / metabolism
Liver Neoplasms / genetics
Liver Neoplasms / metabolism*
Liver Neoplasms / pathology
Lung Neoplasms / metabolism
Lung Neoplasms / secondary
Male
Matrix Attachment Region Binding Proteins / genetics
Matrix Attachment Region Binding Proteins / metabolism*
Mice
Middle Aged
Neoplasm Invasiveness
Phosphorylation
RNA Interference
Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
Transcription Factor AP-1 / metabolism
Transcription, Genetic
Transfection
Up-Regulation

Substances

Calcium-Binding Proteins
Calmodulin
Matrix Attachment Region Binding Proteins
SATB1 protein, human
Transcription Factor AP-1
HRC protein, human
Focal Adhesion Kinase 1
PTK2 protein, human
JNK Mitogen-Activated Protein Kinases
Sarcoplasmic Reticulum Calcium-Transporting ATPases
ATP2A2 protein, human