HDGF-related protein-3 is required for anchorage-independent survival and chemoresistance in hepatocellular carcinomas

Qianyi Xiao, Kai Qu, Chenji Wang, Yahui Kong, Chao Liu, Deke Jiang, Hexige Saiyin, Fan Jia, Canrong Ni, Taoyang Chen, Yuanyuan Zhang, Pingzhao Zhang, Wenxin Qin, Qingwen Sun, Hongyang Wang, Qing Yi, Jun Liu, Haojie Huang, Long Yu

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)440-451
Number of pages12
JournalGut
Volume62
Issue number3
DOIs
StatePublished - Mar 2013

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Hepatocellular Carcinoma
Proteins
Anoikis
Extracellular Signal-Regulated MAP Kinases
hepatoma-derived growth factor
Growth
STAT3 Transcription Factor
JNK Mitogen-Activated Protein Kinases
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Heterografts
Pharmaceutical Preparations
Western Blotting
Immunohistochemistry
Apoptosis
Cell Line
Messenger RNA

ASJC Scopus subject areas

  • Gastroenterology

Cite this

HDGF-related protein-3 is required for anchorage-independent survival and chemoresistance in hepatocellular carcinomas. / Xiao, Qianyi; Qu, Kai; Wang, Chenji; Kong, Yahui; Liu, Chao; Jiang, Deke; Saiyin, Hexige; Jia, Fan; Ni, Canrong; Chen, Taoyang; Zhang, Yuanyuan; Zhang, Pingzhao; Qin, Wenxin; Sun, Qingwen; Wang, Hongyang; Yi, Qing; Liu, Jun; Huang, Haojie; Yu, Long.

In: Gut, Vol. 62, No. 3, 03.2013, p. 440-451.

Research output: Contribution to journalArticle

Xiao, Q, Qu, K, Wang, C, Kong, Y, Liu, C, Jiang, D, Saiyin, H, Jia, F, Ni, C, Chen, T, Zhang, Y, Zhang, P, Qin, W, Sun, Q, Wang, H, Yi, Q, Liu, J, Huang, H & Yu, L 2013, 'HDGF-related protein-3 is required for anchorage-independent survival and chemoresistance in hepatocellular carcinomas', Gut, vol. 62, no. 3, pp. 440-451. https://doi.org/10.1136/gutjnl-2011-300781
Xiao, Qianyi ; Qu, Kai ; Wang, Chenji ; Kong, Yahui ; Liu, Chao ; Jiang, Deke ; Saiyin, Hexige ; Jia, Fan ; Ni, Canrong ; Chen, Taoyang ; Zhang, Yuanyuan ; Zhang, Pingzhao ; Qin, Wenxin ; Sun, Qingwen ; Wang, Hongyang ; Yi, Qing ; Liu, Jun ; Huang, Haojie ; Yu, Long. / HDGF-related protein-3 is required for anchorage-independent survival and chemoresistance in hepatocellular carcinomas. In: Gut. 2013 ; Vol. 62, No. 3. pp. 440-451.
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abstract = "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.",
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T1 - HDGF-related protein-3 is required for anchorage-independent survival and chemoresistance in hepatocellular carcinomas

AU - Xiao, Qianyi

AU - Qu, Kai

AU - Wang, Chenji

AU - Kong, Yahui

AU - Liu, Chao

AU - Jiang, Deke

AU - Saiyin, Hexige

AU - Jia, Fan

AU - Ni, Canrong

AU - Chen, Taoyang

AU - Zhang, Yuanyuan

AU - Zhang, Pingzhao

AU - Qin, Wenxin

AU - Sun, Qingwen

AU - Wang, Hongyang

AU - Yi, Qing

AU - Liu, Jun

AU - Huang, Haojie

AU - Yu, Long

PY - 2013/3

Y1 - 2013/3

N2 - 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.

AB - 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.

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