Abstract
Objective
To investigate how hepatocyte cell adhesion molecule (hepaCAM) regulates cancer energy
metabolism through hypoxia-inducible factor (HIF-1α) in renal cell carcinoma (RCC).
Materials and Methods
The expression of hepaCAM and HIF-1α in RCC tissue samples was examined by immunohistochemistry.
Glucose consumption and lactate production assays were used to detect metabolic activity
in RCC cell lines. P65 and IκB kinase (IKKβ) mRNA and protein expression were detected
using quantitative real-time polymerase chain reaction and western blotting, respectively.
Nuclear translocation of P65 was observed by immunofluorescence staining after re-expressing
hepaCAM. The luciferase reporter assay was applied to validate the transcriptional
activity of HIF-1α.
Results
HIF-1α expression was elevated and hepaCAM suppressed in RCC compared with adjacent
normal tissues. Furthermore, hepaCAM re-expression significantly decreased glycolytic
metabolism in RCC cell lines, and reduced HIF-1α, IKKβ, and P65 expression. The expression
of HIF-1α, GLUT1, LDHA, and PKM2 were further reduced with combined hepaCAM overexpression
and treatment with the NF-κB inhibitor BAY11-7082, compared to hepaCAM overexpression
alone. Additionally, hepaCAM decreased the transcriptional activity of HIF-1α and
blocked P65 nuclear translocation by the NF-κB pathway.
Conclusion
Our data suggest that hepaCAM suppresses the Warburg effect via the HIF-1α/NF-κB pathway
in RCC, which is a facilitating factor in hepaCAM-reduced tumorigenesis.
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References
- Global cancer statistics, 2012.CA Cancer J Clin. 2015; 65: 87-108https://doi.org/10.3322/caac.21262
- Integrated molecular analysis of clear-cell renal cell carcinoma.Nat Genet. 2013; 45: 860-867https://doi.org/10.1038/ng.2699
- Molecular aberrations, targeted therapy, and renal cell carcinoma: current state-of-the-art.Cancer Metastasis Rev. 2014; 33: 1109-1124https://doi.org/10.1007/s10555-014-9533-1
- Cloning and characterization of hepaCAM, a novel Ig-like cell adhesion molecule suppressed in human hepatocellular carcinoma.J Hepatol. 2005; 42: 833-841https://doi.org/10.1016/j.jhep.2005.01.025
- Overexpression of HepaCAM inhibits cell viability and motility through suppressing nucleus translocation of androgen receptor and ERK signaling in prostate cancer.Prostate. 2014; 74: 1023-1033https://doi.org/10.1002/pros.22817
- HepaCAM inhibits clear cell renal carcinoma 786-0 cell proliferation via blocking PKCepsilon translocation from cytoplasm to plasma membrane.Mol Cell Biochem. 2014; 391: 95-102https://doi.org/10.1007/s11010-014-1991-9
- hepaCAM and p-mTOR closely correlate in bladder transitional cell carcinoma and hepaCAM expression inhibits proliferation via an AMPK/mTOR dependent pathway in human bladder cancer cells.J Urol. 2013; 190: 1912-1918https://doi.org/10.1016/j.juro.2013.05.013
- HepaCAM induces G1 phase arrest and promotes c-Myc degradation in human renal cell carcinoma.J Cell Biochem. 2011; 112: 2910-2919https://doi.org/10.1002/jcb.23207
- Regulation and function of pyruvate kinase M2 in cancer.Cancer Lett. 2013; 339: 153-158https://doi.org/10.1016/j.canlet.2013.06.008
- Pyruvate kinase M2 at a glance.J Cell Sci. 2015; 128: 1655-1660https://doi.org/10.1242/jcs.166629
- HIF-1: upstream and downstream of cancer metabolism.Curr Opin Genet Dev. 2010; 20: 51-56https://doi.org/10.1016/j.gde.2009.10.009
- Generation of a mouse model of Von Hippel-Lindau kidney disease leading to renal cancers by expression of a constitutively active mutant of HIF1alpha.Cancer Res. 2011; 71: 6848-6856https://doi.org/10.1158/0008-5472.can-11-1745
- Bevacizumab treatment for solid tumors: boon or bust?.JAMA. 2011; 305: 506-508https://doi.org/10.1001/jama.2011.57
- Regulation of glucose metabolism by p62/SQSTM1 through HIF1alpha.J Cell Sci. 2016; 129: 817-830https://doi.org/10.1242/jcs.178756
- How NF-kappaB is activated: the role of the IkappaB kinase (IKK) complex.Oncogene. 1999; 18: 6867-6874https://doi.org/10.1038/sj.onc.1203219
- Understanding the Warburg effect: the metabolic requirements of cell proliferation.Science. 2009; 324: 1029-1033https://doi.org/10.1126/science.1160809
van Uden, P., N.S. Kenneth, and S. Rocha, Regulation of hypoxia-inducible factor-1alpha by NF-kappaB. Biochem J, 2008,412:477-484 DOI: 10.1042/bj20080476.
- On the origin of cancer cells.Science. 1956; 123: 309-314
- Untuning the tumor metabolic machine: HIF-alpha: pro- and antitumorigenic?.Nat Med. 2012; 18: 1024-1025https://doi.org/10.1038/nm.2865
- Interleukin 6 induces cell proliferation of clear cell renal cell carcinoma by suppressing hepaCAM via the STAT3-dependent up-regulation of DNMT1 or DNMT3b.Cell Signal. 2017; 32: 48-58https://doi.org/10.1016/j.cellsig.2017.01.017
- FAT1 is a novel upstream regulator of HIF1alpha and invasion of high grade glioma.Int J Cancer. 2016; 139: 2570-2582https://doi.org/10.1002/ijc.30386
- Cbx4 governs HIF-1alpha to potentiate angiogenesis of hepatocellular carcinoma by its SUMO E3 ligase activity.Cancer Cell. 2014; 25: 118-131https://doi.org/10.1016/j.ccr.2013.12.008
- O-GlcNAcylation regulates cancer metabolism and survival stress signaling via regulation of the HIF-1 pathway.Mol Cell. 2014; 54: 820-831https://doi.org/10.1016/j.molcel.2014.04.026
- mTOR inhibition reverses AKT-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways.Nat Med. 2004; 10: 594-601https://doi.org/10.1038/nm1052
- Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1.Cell Growth Differ. 2001; 12: 363-369
- Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics.Cancer Res. 2000; 60: 1541-1545
- Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer.Nat Med. 2006; 12: 122-127https://doi.org/10.1038/nm1337
- NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha.Nature. 2008; 453: 807-811https://doi.org/10.1038/nature06905
Article info
Publication history
Published online: December 04, 2018
Accepted:
November 27,
2018
Received:
September 20,
2018
Footnotes
Financial Disclosure: The authors declare that they have no relevant financial interests.
Ethical Approval: In our study, all of the assays association with human participants conformed, respectively, to the ethical standards of the institutional and national research committee, to the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Ethics Committee of Chongqing Medical University consented to our study.
Identification
Copyright
© 2018 Elsevier Inc. All rights reserved.
