HDGF-related protein-3 is required for anchorage-independent survival and chemoresistance in hepatocellular carcinomas
- Qianyi Xiao1,
- Kai Qu1,
- Chenji Wang1,
- Yahui Kong1,
- Chao Liu1,
- Deke Jiang1,
- Hexige Saiyin1,
- Fan Jia2,
- Canrong Ni3,
- Taoyang Chen4,
- Yuanyuan Zhang1,
- Pingzhao Zhang1,
- Wenxin Qin5,
- Qingwen Sun1,
- Hongyang Wang6,
- Qing Yi7,
- Jun Liu8,
- Haojie Huang9,
- Long Yu1,10
- 1State Key Laboratory of Genetic Engineering, Shanghai, People's Republic of China
- 2Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Shanghai, People's Republic of China
- 3Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China
- 4Qi Dong Liver Cancer Institute, Qi Dong, Jiangsu, People's Republic of China
- 5Department of Experimental Pathology, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- 6Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, People's Republic of China
- 7Department of Lymphoma and Myeloma, Center for Cancer Immunology Research, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- 8Departments of Pharmacology and Molecular Sciences and Oncology, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA
- 9Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
- 10Institutes of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China
- Correspondence to Dr Long Yu, The State Key Laboratory of Genetic Engineering, Fudan University, 220 Handan Road, Shanghai 200433, People's Republic of China;
Contributors KQ, XY, CW and YK performed most experiments, CL and DJ performed reverse transcriptase PCR analysis. HS, CN, YZ and PZ performed immunohistochemistry analysis. QS, JF, TC, WQ and HW collected clinical tumour samples. QY, JOL, HH and LY wrote the manuscript. LY supervised the work.
- Revised 16 January 2012
- Accepted 21 January 2012
- Published Online First 5 April 2012
Objective Hepatoma-derived growth factor (HDGF)-related proteins (HRPs) comprise a family of six members and are characterised by a conserved HATH domain. Among the family members, HDGF was the first to be identified as a mitogenic factor and shown to play an important role in hepatocellular carcinoma pathogenesis. The aim of the present study is to examine the relevance of HDGF-related protein-3 (HRP-3), another member of the HRP family in hepatocellular carcinoma (HCC).
Design HRP-3 expression in HCC tissues was measured by quantitative reverse transcriptase PCR, western blot and immunohistochemistry analysis. The biological consequences of overexpression and knockdown of HRP-3 in HCC cell lines were studied in vitro and in vivo.
Results Expression of HRP-3 mRNA and protein was shown to be highly upregulated in HCC tissues. While knockdown of HRP-3 by small interference RNAs failed to affect anchorage-dependent growth of HCC cells, it inhibited anchorage-independent growth of HCC cells in vitro and xenograft tumour growth in vivo. Further, knockdown of HRP-3 was shown to sensitise HCC cells to anoikis. Moreover, HRP-3 specifically activated the extracellular-signal-regulated kinase (ERK) pathway without affecting c-Jun N-terminal kinase (JNK), p38, AKT and signal transducer and activator of transcription 3 (STAT3). Importantly, inhibition of the ERK pathway diminished HRP-3-mediated protection of HCC cells from anoikis. Finally, knockdown of HRP-3 was shown to enhance apoptosis of HCC cells induced by multiple chemotherapeutic drugs.
Conclusion These findings indicate that HRP-3 plays an essential role in HCC pathogenesis and suggest that it may serve as a novel prognostic marker and molecular target for development of drugs for treatment of HCC.
- ERK activation
- hepatocellular carcinoma
- liver, liver cirrhosis
- cell biology
- cancer prevention
- hepatic transport
- hepatic surgery
- hepatobiliary cancer
- cell signalling
QX, KQ and CW contributed equally to this work.
Funding This work was supported by the National Key Sci-Tech Special Project of China (2008ZX10002-020, 2008ZX10002-021), National Natural Science Foundation of China (30872947), Changjiang Visiting Scholars Program (Qing Yi and Jun O. Liu).
Competing interests None.
Patient consent Obtained.
Ethics approval This work was done with the approval of the Medical Ethics Committee of Fudan University.
Provenance and peer review Not commissioned; externally peer reviewed.