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SPOCK1 is regulated by CHD1L and blocks apoptosis and promotes HCC cell invasiveness and metastasis in mice
Yan Li1, Leilei Chen, Tim Hon Man Chan
1Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.
Background & Aims:
Chromodomain helicase/adenosine triphosphatase DNA binding protein 1-like (CHD1L) is an SNF2-like transcription factor involved in the development of human hepatocellular carcinoma (HCC). Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) is up-regulated by CHD1L; we investigated its role in hepatocellular carcinogenesis.
Methods:
We investigated interactions between SPOCK1 and CHD1L using electrophoretic mobility shift and luciferase reporter assays. Levels of SPOCK1 messenger RNA (mRNA) and protein were measured in samples of HCC and adjacent nontumor liver tissues (135 pairs) and compared using Pearson correlation coefficients. Effects of SPOCK1 overexpression and silencing were determined in HCC cell lines (QGY-7703, PLC-8024, BEL-7402, and QGY-7701).
Results:
The CHD1L protein bound directly to the promoter region (nt-1662 to +34) of SPOCK1 and activated transcription. Levels of SPOCK1 mRNA and protein were increased in 60% of human HCC samples, compared with nontumor live tissues, and was associated significantly with clinical stage. Levels of SPOCK1 mRNA were increased among tumors that became metastatic, compared with those that did not, and among patients with shorter overall and disease-free survival times. Ectopic expression of SPOCK1 in HCC cells increased proliferation, foci formation, and colony formation in soft agar; these cells also formed larger xenograft tumors, more rapidly, in nude mice than control HCC cells. Silencing SPOCK1 expression with short hairpin RNA had the opposite effects. We found that SPOCK1 prevents apoptosis of HCC cells by activating Akt, to block release of cytochrome c and activation of caspase-9 and caspase-3; these effects were reversed with an Akt inhibitor. HCC cells that overexpressed SPOCK1 expressed higher levels of matrix metallopeptidase 9, were more invasive in Matrigel assays, and formed more metastatic nodules in immunodeficient mice than control HCC cells.
Conclusions:
CHD1L activates expression of SPOCK1, which activates Akt signaling to block apoptosis and invasion by HCC cells, in culture and in mice. Levels of SPOCK1 increase with progression of human HCC. SPOCK1 might be used as a prognostic factor or therapeutic target.
Insights
Chromodomain helicase/adenosine triphosphatase DNA binding protein 1-like (CHD1L) activates SPOCK1, a protein that promotes hepatocellular carcinoma (HCC) progression by inhibiting apoptosis and increasing invasion. SPOCK1 may serve as a therapeutic target for HCC.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Chromodomain helicase/adenosine triphosphatase DNA binding protein 1-like (CHD1L) is implicated in hepatocellular carcinoma (HCC) development.
- SPOCK1 is upregulated by CHD1L, suggesting a role in HCC pathogenesis.
Purpose of the Study:
- To investigate the interaction between CHD1L and SPOCK1.
- To elucidate the role of SPOCK1 in hepatocellular carcinogenesis.
Main Methods:
- Electrophoretic mobility shift and luciferase reporter assays were used to study SPOCK1-CHD1L interactions.
- SPOCK1 mRNA and protein levels were quantified in HCC tissues and cell lines.
- Functional effects of SPOCK1 modulation were assessed in HCC cell lines and xenograft models.
Main Results:
- CHD1L directly binds and activates the SPOCK1 promoter.
- SPOCK1 expression is elevated in HCC tissues and correlates with clinical stage, metastasis, and poorer survival.
- SPOCK1 overexpression enhances HCC cell proliferation, invasion, and tumor growth by activating Akt signaling and inhibiting apoptosis.
Conclusions:
- CHD1L-induced SPOCK1 activation promotes HCC progression by blocking apoptosis and enhancing invasion.
- Elevated SPOCK1 levels in HCC suggest its potential as a prognostic marker and therapeutic target.
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