HDGF-related protein-3 is required for anchorage-independent survival and chemoresistance in hepatocellular carcinomas
| Autor: | Fan Jia, Haojie Huang, Tao-Yang Chen, Hongyang Wang, Chao Liu, Qingwen Sun, Hexige Saiyin, Deke Jiang, Pingzhao Zhang, Qing Yi, Long Yu, Kai Qu, Wenxin Qin, Qianyi Xiao, Ya-Hui Kong, Jun O. Liu, Yuanyuan Zhang, Canrong Ni, Chenji Wang |
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| Rok vydání: | 2012 |
| Předmět: |
MAPK/ERK pathway
Carcinoma Hepatocellular medicine.medical_treatment Blotting Western Mice Nude In Vitro Techniques Biology Mice Cell Line Tumor medicine Animals Humans Anoikis RNA Messenger Extracellular Signal-Regulated MAP Kinases STAT3 Protein kinase B Cell Proliferation Gene knockdown Reverse Transcriptase Polymerase Chain Reaction Cell growth Growth factor Liver Neoplasms Intracellular Signaling Peptides and Proteins Gastroenterology Nuclear Proteins Immunohistochemistry Molecular biology digestive system diseases Up-Regulation Enzyme Activation Cytoskeletal Proteins Gene Expression Regulation Drug Resistance Neoplasm Gene Knockdown Techniques STAT protein Cancer research biology.protein |
| Zdroj: | Gut. 62:440-451 |
| ISSN: | 1468-3288 0017-5749 |
| DOI: | 10.1136/gutjnl-2011-300781 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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