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
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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.
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