Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Tumor Biology
Published in: Tumor Biology 10/2016

01-10-2016 | Original Article

Extracellular HSP70-peptide complexes promote the proliferation of hepatocellular carcinoma cells via TLR2/4/JNK1/2MAPK pathway

Authors: Yi Zhe, Yan Li, Dan Liu, Dong-Ming Su, Jin-Gang Liu, Hang-Yu Li

Published in: Tumor Biology | Issue 10/2016

Login to get access

Abstract

Heat shock protein 70 (HSP70) and HSP70-peptide complexes (HSP70-PCs) have been implicated in the pathogenesis of multiple tumors in humans and have been experimentally shown to increase the proliferation of cell lines derived from hepatocellular carcinoma. The goal of this study was to elucidate the molecular mechanisms through which extracellular HSP70/HSP70-PCs stimulate the proliferation of hepatocellular carcinoma (HCC). The molecular mechanisms of HSP70/HSP70-PC action were studied in the human hepatocellular carcinoma cell lines HepG2 and Huh-7, as well as tumor tissue collected from patients with HCC (n = 95). We found that HSP70/HSP70-PCs can stimulate the proliferation of HepG2 cells and that this effect is blocked by knocking down TLR2 and TLR4 expression by RNA interference. A physical interaction between HSP70/HSP70-PCs and TLR2/4 was established using co-immunoprecipitation and pull-down assays. Pharmacological inhibition of different branches of the MAPK intracellular signaling pathway indicated that the extracellular HSP70/HSP70-PC effect was mediated by the JNK1/2 signaling pathway within the cell. We also studied TLR2 and TLR expression at the protein and messenger RNA (mRNA) level in tumor and non-tumor tissue in patients with HCC (n = 95), finding that TLR2 and 4 are increased in HCC tumor tissue and that the expression of TLR2 correlates with clinicopathologic features of HCC. Our data conclusively demonstrates that extracellular HSP70/HSP70-PCs can promote the proliferation of HCC cells through activation of TLR2 and TLR4 and subsequent activation of the intracellular JNK1/2/MAPK signaling pathway.
Appendix
Available only for authorised users
Literature
1.
2.
Chen JG, Zhang SW. Liver cancer epidemic in China: past, present and future. Semin Cancer Biol. 2011;21(1):59–69.CrossRefPubMed
3.
4.
Duffy DJ, Millane RC, Frank U. A heat shock protein and Wnt signaling crosstalk during axial patterning and stem cell proliferation. Dev Biol. 2012;362(2):271–81.CrossRefPubMed
5.
6.
Gogate SS et al. Tonicity enhancer binding protein (TonEBP) and hypoxia-inducible factor (HIF) coordinate heat shock protein 70 (Hsp70) expression in hypoxic nucleus pulposus cells: role of Hsp70 in HIF-1alpha degradation. J Bone Miner Res. 2012;27(5):1106–17.CrossRefPubMedPubMedCentral
7.
Horibe T et al. Synergetic cytotoxic activity toward breast cancer cells enhanced by the combination of Antp-TPR hybrid peptide targeting Hsp90 and Hsp70-targeted peptide. BMC Cancer. 2014;14:615.CrossRefPubMedPubMedCentral
8.
Schmitt E et al. Intracellular and extracellular functions of heat shock proteins: repercussions in cancer therapy. J Leukoc Biol. 2007;81(1):15–27.CrossRefPubMed
9.
Wu FH et al. Extracellular HSPA1A promotes the growth of hepatocarcinoma by augmenting tumor cell proliferation and apoptosis-resistance. Cancer Lett. 2012;317(2):157–64.CrossRefPubMed
10.
Asea A et al. Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem. 2002;277(17):15028–34.CrossRefPubMed
11.
Murphy MB, Medvedev AE. Long noncoding RNAs as regulators of Toll-like receptor signaling and innate immunity. J Leukoc Biol. 2016.
12.
Chen L, Yu J. Modulation of Toll-like receptor signaling in innate immunity by natural products. Int Immunopharmacol. 2016.
13.
Tsai SY et al. DAMP molecule S100 A9 acts as a molecular pattern to enhance inflammation during influenza a virus infection: role of DDX21-TRIF-TLR4-MyD88 pathway. PLoS Pathog. 2014;10(1):e1003848.CrossRefPubMedPubMedCentral
14.
Henrick BM et al. HIV-1 structural proteins serve as PAMPs for TLR2 heterodimers significantly increasing infection and innate immune activation. Front Immunol. 2015;6:426.PubMedPubMedCentral
15.
Leake I. Hepatocellular carcinoma. Treatment potential of targeting Toll-like receptors in HCC. Nat Rev. Gastroenterol Hepatol. 2014;11(9):518.
16.
Chen R et al. Cancers take their Toll—the function and regulation of toll-like receptors in cancer cells. Oncogene. 2008;27(2):225–33.CrossRefPubMed
17.
Yue P et al. Des-gamma-carboxyl prothrombin induces matrix metalloproteinase activity in hepatocellular carcinoma cells by involving the ERK1/2 MAPK signalling pathway. Eur J Cancer. 2011;47(7):1115–24.CrossRefPubMed
18.
Huang Y, et al. MAPK/ERK2 phosphorylates ERG at serine 283 in leukemic cells and promotes stem cell signatures and cell proliferation. Leukemia. 2016.
19.
Kamiyama M, Naguro I, Ichijo H. In vivo gene manipulation reveals the impact of stress-responsive MAPK pathways on tumor progression. Cancer Sci. 2015;106(7):785–96.CrossRefPubMedPubMedCentral
20.
21.
Wu TT et al. GATA-2 transduces LPS-induced il-1beta gene expression in macrophages via a toll-like receptor 4/MD88/MAPK-dependent mechanism. PLoS One. 2013;8(8):e72404.CrossRefPubMedPubMedCentral
22.
23.
Zhang Y et al. A systematic investigation based on microRNA-mediated gene regulatory network reveals that dysregulation of microRNA-19a/cyclin D1 axis confers an oncogenic potential and a worse prognosis in human hepatocellular carcinoma. RNA Biol. 2015;12(6):643–57.CrossRefPubMedPubMedCentral
24.
Qiu C et al. GM-CSF induces cyclin D1 expression and proliferation of endothelial progenitor cells via PI3K and MAPK signaling. Cell Physiol Biochem. 2014;33(3):784–95.CrossRefPubMed
25.
Gao Y et al. A new purification method for enhancing the immunogenicity of heat shock protein 70-peptide complexes. Oncol Rep. 2012;28(6):1977–83.PubMedPubMedCentral
26.
Li H et al. Expression of HSP70 and JNK-related proteins in human liver cancer: potential effects on clinical outcome. Dig Liver Dis. 2007;39(7):663–70.CrossRefPubMed
27.
Blachere NE et al. Heat shock protein-peptide complexes, reconstituted in vitro, elicit peptide-specific cytotoxic T lymphocyte response and tumor immunity. J Exp Med. 1997;186(8):1315–22.CrossRefPubMedPubMedCentral
28.
Casaburi I et al. Chenodeoxycholic acid through a TGR5-dependent CREB signaling activation enhances cyclin D1 expression and promotes human endometrial cancer cell proliferation. Cell Cycle. 2012;11(14):2699–710.CrossRefPubMed
29.
Kiang JG, Tsokos GC. Heat shock protein 70 kDa: molecular biology, biochemistry, and physiology. Pharmacol Ther. 1998;80(2):183–201.CrossRefPubMed
30.
31.
Gong W et al. Invasion potential of H22 hepatocarcinoma cells is increased by HMGB1-induced tumor NF-kappaB signaling via initiation of HSP70. Oncol Rep. 2013;30(3):1249–56.PubMed
32.
Monma H et al. The HSP70 and autophagy inhibitor pifithrin-mu enhances the antitumor effects of TRAIL on human pancreatic cancer. Mol Cancer Ther. 2013;12(4):341–51.CrossRefPubMed
33.
Mambula SS, Calderwood SK. Heat shock protein 70 is secreted from tumor cells by a nonclassical pathway involving lysosomal endosomes. J Immunol. 2006;177(11):7849–57.CrossRefPubMed
34.
Bohnhorst J et al. Toll-like receptors mediate proliferation and survival of multiple myeloma cells. Leukemia. 2006;20(6):1138–44.CrossRefPubMed
35.
36.
Lee CH, Wu CL, Shiau AL. Toll-like receptor 4 signaling promotes tumor growth. J Immunother. 2010;33(1):73–82.CrossRefPubMed
37.
Yu L, Wang L, Chen S. Dual character of toll-like receptor signaling: pro-tumorigenic effects and anti-tumor functions. Biochim Biophys Acta. 2013;1835(2):144–54.PubMed
38.
39.
Kim JY et al. Sulforaphane suppresses vascular adhesion molecule-1 expression in TNF-alpha-stimulated mouse vascular smooth muscle cells: involvement of the MAPK, NF-kappaB and AP-1 signaling pathways. Vasc Pharmacol. 2012;56(3–4):131–41.CrossRef
Metadata
Title
Extracellular HSP70-peptide complexes promote the proliferation of hepatocellular carcinoma cells via TLR2/4/JNK1/2MAPK pathway
Authors
Yi Zhe
Yan Li
Dan Liu
Dong-Ming Su
Jin-Gang Liu
Hang-Yu Li
Publication date
01-10-2016
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 10/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-016-5189-5

Other articles of this Issue 10/2016

Tumor Biology 10/2016 Go to the issue

Original Article

HSP90B1 overexpression predicts poor prognosis in NSCLC patients

Original Article

MicroRNA-106b promotes pituitary tumor cell proliferation and invasion through PI3K/AKT signaling pathway by targeting PTEN

Original Article

Rab11a sustains GSK3β/Wnt/β-catenin signaling to enhance cancer progression in pancreatic cancer

Original Article

Different expression levels of glycans on leukemic cells—a novel screening method with molecularly imprinted polymers (MIP) targeting sialic acid

Original Article

Clinicopathological and prognostic significance of Yes-associated protein expression in hepatocellular carcinoma and hepatic cholangiocarcinoma

Original Article

Knockdown of USP39 induces cell cycle arrest and apoptosis in melanoma
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits