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

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Cancer Cell International
Published in: Cancer Cell International 1/2015

Open Access 01-12-2015 | Primary research

B7-H3 promotes aggression and invasion of hepatocellular carcinoma by targeting epithelial-to-mesenchymal transition via JAK2/STAT3/Slug signaling pathway

Authors: Fu-biao Kang, Ling Wang, Heng-chuan Jia, Dong Li, Hai-jun Li, Yin-ge Zhang, Dian-xing Sun

Published in: Cancer Cell International | Issue 1/2015

Login to get access

Abstract

Background

B7-homologue 3 (B7-H3), a recently identified immunoregulatory protein, has been shown to be overexpressed in human hepatocellular carcinoma (HCC). However, whether the dynamic expression pattern of B7-H3 contributes to early invasion of HCC is largely unknown. In addition, the biological roles of B7-H3 in HCC are still unclear. Herein, we are going to examine B7-H3 expression profile and its clinicopathological significance in primary and metastatic HCC, and further determine whether B7-H3 knockdown simulates different pathological states of HCC progression and metastasis.

Methods

Using immunohistochemistry, B7-H3 expression was studied on 116 HCC containing primary and metastatic HCCs. Survival curves and log-rank tests were used to test the association of B7-H3 expression with survival. HCC cells with B7-H3 depletion were established by RNA interference to investigate the effect of B7-H3 on cell proliferation, apoptosis, migration and invasion in vitro.

Results

Statistical analysis of clinical cases revealed that B7-H3 high expression group had inclinations towards late TNM stage, the presence of vascular invasion, lymph metastasis, and the formation of microsatellite tumors. Increased intensity of tumor B7-H3 staining was detected more significantly in metastatic HCC tumors. Consistently in experiments performed in vitro, B7-H3 was able to stimulate the wound healing, metastasis and invasion of hepatoma cells by targeting epithelial-to-mesenchymal transition (EMT) via JAK2/Stat3/Slug signaling pathway, while no obvious influence on cell growth and apoptosis.

Conclusion

B7-H3 in the regulation of the metastatic capacity of HCC cells makes itself a promising therapeutic target for anti-metastasis therapy.
Appendix
Available only for authorised users
Literature
1.
Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet. 2002;31(4):339–46.CrossRefPubMed
2.
Wang H, Chen L. Tumor microenviroment and hepatocellular carcinoma metastasis. J Gastroenterol Hepatol. 2013;28 Suppl 1:43–8.CrossRefPubMed
3.
Auguste P, Fallavollita L, Wang N, Burnier J, Bikfalvi A, Brodt P. The host inflammatory response promotes liver metastasis by increasing tumor cell arrest and extravasation. Am J Pathol. 2007;170(5):1781–92.CrossRefPubMedCentralPubMed
4.
Barkan D, El Touny LH, Michalowski AM, Smith JA, Chu I, Davis AS, et al. Metastatic growth from dormant cells induced by a col-I-enriched fibrotic environment. Cancer Res. 2010;70(14):5706–16.CrossRefPubMedCentralPubMed
5.
Barkan D, Kleinman H, Simmons JL, Asmussen H, Kamaraju AK, Hoenorhoff MJ, et al. Inhibition of metastatic outgrowth from single dormant tumor cells by targeting the cytoskeleton. Cancer Res. 2008;68(15):6241–50.CrossRefPubMedCentralPubMed
6.
Chapoval AI, Ni J, Lau JS, Wilcox RA, Flies DB, Liu D, et al. B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. Nature Immunol. 2001;2(3):269–74.CrossRef
7.
Crispen PL, Sheinin Y, Roth TJ, Lohse CM, Kuntz SM, Frigola X, et al. Tumor cell and tumor vasculature expression of B7-H3 predict survival in clear cell renal cell carcinoma. Clin Cancer Res. 2008;14(16):5150–7.CrossRefPubMedCentralPubMed
8.
Castriconi R, Dondero A, Augugliaro R, Cantoni C, Carnemolla B, Sementa AR, et al. Identification of 4Ig-B7-H3 as a neuroblastoma-associated molecule that exerts a protective role from an NK cell-mediated lysis. Proc Natl Acad Sci U S A. 2004;101(34):12640–5.CrossRefPubMedCentralPubMed
9.
Wang L, Kang FB, Shan BE. B7-H3-mediated tumor immunology: friend or foe? Int J Cancer. 2014;134(12):2764–71.CrossRefPubMed
10.
Luo L, Chapoval AI, Flies DB, Zhu G, Hirano F, Wang S, et al. B7-H3 enhances tumor immunity in vivo by costimulating rapid clonal expansion of antigen-specific CD8+ cytolytic T cells. J Immunol. 2004;173(9):5445–50.CrossRefPubMed
11.
Prasad DV, Nguyen T, Li Z, Yang Y, Duong J, Wang Y, et al. Murine B7-H3 is a negative regulator of T cells. J Immunol. 2004;173(4):2500–6.CrossRefPubMed
12.
Suh WK, Gajewska BU, Okada H, Gronski MA, Bertram EM, Dawicki W, et al. The B7 family member B7-H3 preferentially down-regulates T helper type 1-mediated immune responses. Nat Immunol. 2003;4(9):899–906.CrossRefPubMed
13.
Yuan H, Wei X, Zhang G, Li C, Zhang X, Hou J. B7-H3 over expression in prostate cancer promotes tumor cell progression. J Urol. 2011;186(3):1093–9.CrossRefPubMed
14.
Zhao X, Li DC, Zhu XG, Gan WJ, Li Z, Xiong F, et al. B7-H3 overexpression in pancreatic cancer promotes tumor progression. Int J Mol Med. 2013;31(2):283–91.PubMedCentralPubMed
15.
Sun TW, Gao Q, Qiu SJ, Zhou J, Wang XY, Yi Y, et al. B7-H3 is expressed in human hepatocellular carcinoma and is associated with tumor aggressiveness and postoperative recurrence. Cancer Immunol Immunother. 2012;61(11):2171–82.CrossRefPubMed
16.
Chen YW, Tekle C, Fodstad O. The immunoregulatory protein human B7H3 is a tumor-associated antigen that regulates tumor cell migration and invasion. Curr Cancer Drug Targets. 2008;8(5):404–13.CrossRefPubMed
17.
Liu RY, Zeng Y, Lei Z, Wang L, Yang H, Liu Z, et al. JAK/STAT3 signaling is required for TGF-beta-induced epithelial-mesenchymal transition in lung cancer cells. Int J Oncol. 2014;44(5):1643–51.PubMed
18.
19.
Lo HW, Hsu SC, Xia W, Cao X, Shih JY, Wei Y, et al. Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Cancer Res. 2007;67(19):9066–76.CrossRefPubMedCentralPubMed
20.
Li F, Guo Z, Wang H. Influencing elements and treatment strategies associated with the relapse of hepatocellular carcinoma after surgery. Hepato-Gastroenterology. 2013;60(125):1148–55.PubMed
21.
22.
Janakiram M, Abadi YM, Sparano JA, Zang X. T cell coinhibition and immunotherapy in human breast cancer. Discov Med. 2012;14(77):229–36.PubMedCentralPubMed
23.
Liu H, Tekle C, Chen YW, Kristian A, Zhao Y, Zhou M, et al. B7-H3 silencing increases paclitaxel sensitivity by abrogating Jak2/Stat3 phosphorylation. Mol Cancer Ther. 2011;10(6):960–71.CrossRefPubMedCentralPubMed
24.
Nygren MK, Tekle C, Ingebrigtsen VA, Fodstad O. B7-H3 and its relevance in cancer; immunological and non-immunological perspectives. Front Biosci (Elite Ed). 2011;3:989–93.PubMed
25.
Mierke CT. Physical break-down of the classical view on cancer cell invasion and metastasis. Eur J Cell Biol. 2013;92(3):89–104.CrossRefPubMed
26.
Hadler-Olsen E, Winberg JO, Uhlin-Hansen L. Matrix metalloproteinases in cancer: their value as diagnostic and prognostic markers and therapeutic targets. Tumour Biol. 2013;34(4):2041–51.CrossRefPubMed
27.
Li X, Yang Z, Song W, Zhou L, Li Q, Tao K, et al. Overexpression of Bmi-1 contributes to the invasion and metastasis of hepatocellular carcinoma by increasing the expression of matrix metalloproteinase (MMP) 2, MMP-9 and vascular endothelial growth factor via the PTEN/PI3K/Akt pathway. Int J Oncol. 2013;43(3):793–802.PubMed
28.
Chen JS, Huang XH, Wang Q, Huang JQ, Zhang LJ, Chen XL, et al. Sonic hedgehog signaling pathway induces cell migration and invasion through focal adhesion kinase/AKT signaling-mediated activation of matrix metalloproteinase (MMP)-2 and MMP-9 in liver cancer. Carcinogenesis. 2013;34(1):10–9.CrossRefPubMed
29.
Wang L, Zhang Q, Chen W, Shan B, Ding Y, Zhang G, et al. B7-H3 is overexpressed in patients suffering osteosarcoma and associated with tumor aggressiveness and metastasis. PLoS One. 2013;8(8):e70689.CrossRefPubMedCentralPubMed
30.
Tekle C, Nygren MK, Chen YW, Dybsjord I, Nesland JM, Maelandsmo GM, et al. B7-H3 contributes to the metastatic capacity of melanoma cells by modulation of known metastasis-associated genes. Int J Cancer. 2012;130(10):2282–90.CrossRefPubMed
31.
Smith HA, Kang Y. The metastasis-promoting roles of tumor-associated immune cells. J Mol Med (Berl). 2013;91(4):411–29.CrossRef
32.
Man YG, Stojadinovic A, Mason J, Avital I, Bilchik A, Bruecher B, et al. Tumor-infiltrating immune cells promoting tumor invasion and metastasis: existing theories. J Cancer Educ. 2013;4(1):84–95.CrossRef
33.
Yue Y, Shao Y, Luo Q, Shi L, Wang Z. Downregulation of ADAM10 expression inhibits metastasis and invasiveness of human hepatocellular carcinoma HepG2 cells. BioMed Res Int. 2013;2013:434561.CrossRefPubMedCentralPubMed
34.
Yadav A, Kumar B, Datta J, Teknos TN, Kumar P. IL-6 promotes head and neck tumor metastasis by inducing epithelial-mesenchymal transition via the JAK-STAT3-SNAIL signaling pathway. Mol Cancer Res. 2011;9(12):1658–67.CrossRefPubMedCentralPubMed
Metadata
Title
B7-H3 promotes aggression and invasion of hepatocellular carcinoma by targeting epithelial-to-mesenchymal transition via JAK2/STAT3/Slug signaling pathway
Authors
Fu-biao Kang
Ling Wang
Heng-chuan Jia
Dong Li
Hai-jun Li
Yin-ge Zhang
Dian-xing Sun
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2015
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-015-0195-z

Other articles of this Issue 1/2015

Cancer Cell International 1/2015 Go to the issue

Primary research

Stromal-epithelial responses to fractionated radiotherapy in a breast cancer microenvironment

Primary research

MicroR-545 enhanced radiosensitivity via suppressing Ku70 expression in Lewis lung carcinoma xenograft model

Primary research

Celastrol induces cell cycle arrest by MicroRNA-21-mTOR-mediated inhibition p27 protein degradation in gastric cancer

Review

Xanthorrhizol: a review of its pharmacological activities and anticancer properties

Primary research

MiR-124 suppresses cell motility and adhesion by targeting talin 1 in prostate cancer cells

Primary research

Transient knockdown-mediated deficiency in plectin alters hepatocellular motility in association with activated FAK and Rac1-GTPase
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