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 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2012

Open Access 01-12-2012 | Research article

Development of a gene therapy strategy to target hepatocellular carcinoma based inhibition of protein phosphatase 2A using the α-fetoprotein promoter enhancer and pgk promoter: an in vitro and in vivo study

Authors: Wei Li, Dao-Ming Li, Kai Chen, Zheng Chen, Yang Zong, Hong Yin, Ze-Kuan Xu, Yi Zhu, Fei-Ran Gong, Min Tao

Published in: BMC Cancer | Issue 1/2012

Login to get access

Abstract

Background

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Current therapies are insufficient, making HCC an intractable disease. Our previous studies confirmed that inhibition of protein phosphatase 2A (PP2A) may provide a promising therapeutic strategy for cancer. Unfortunately, constitutive expression of PP2A in normal tissues limits the application of PP2A inhibition. Thus, a HCC-specific gene delivery system should be developed. The α-fetoprotein (AFP) promoter is commonly used in HCC-specific gene therapy strategies; however, the utility of this approach is limited due to the weak activity of the AFP promoter. It has been shown that linking the AFP enhancer with the promoter of the non-tissue-specific, human housekeeping phosphoglycerate kinase (pgk) gene can generate a strong and HCC-selective promoter.

Methods

We constructed a HCC-specific gene therapy system to target PP2A using the AFP enhancer/pgk promoter, and evaluated the efficiency and specificity of this system both in vitro and in vivo.

Results

AFP enhancer/pgk promoter-driven expression of the dominant negative form of the PP2A catalytic subunit α (DN-PP2Acα) exerted cytotoxic effects against an AFP-positive human hepatoma cell lines (HepG2 and Hep3B), but did not affect AFP-negative human hepatoma cells (SK-HEP-1) or normal human liver cells (L-02). Moreover, AFP enhancer/pgk promoter driven expression of DN-PP2Acα inhibited the growth of AFP-positive HepG2 tumors in nude mice bearing solid tumor xenografts, but did not affect AFP-negative SK-HEP-1 tumors.

Conclusions

The novel approach of AFP enhancer/pgk promoter-driven expression of DN-PP2Acα may provide a useful cancer gene therapy strategy to selectively target HCC.
Appendix
Available only for authorised users
Literature
1.
Orito E, Mizokami M: Differences of HBV genotypes and hepatocellular carcinoma in Asian countries. Hepatol Res. 2007, 37 (s1): S33-35. 10.1111/j.1872-034X.2007.00101.x.CrossRefPubMed
2.
Hainaut P, Boyle P: Curbing the liver cancer epidemic in Africa. Lancet. 2008, 371 (9610): 367-368. 10.1016/S0140-6736(08)60181-6.CrossRefPubMed
3.
Farazi PA, DePinho RA: Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 2006, 6 (9): 674-687. 10.1038/nrc1934.CrossRefPubMed
4.
Parkin DM, Bray F, Ferlay J, Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 2005, 55 (2): 74-108. 10.3322/canjclin.55.2.74.CrossRefPubMed
5.
Xu Z, Fan X, Xu Y, Di Bisceglie AM: Comparative analysis of nearly full-length hepatitis C virus quasispecies from patients experiencing viral breakthrough during antiviral therapy: clustered mutations in three functional genes, E2, NS2, and NS5a. J Virol. 2008, 82 (19): 9417-9424. 10.1128/JVI.00896-08.CrossRefPubMedPubMedCentral
6.
Wang GS: Medical uses of mylabris in ancient China and recent studies. J Ethnopharmacol. 1989, 26 (2): 147-162. 10.1016/0378-8741(89)90062-7.CrossRefPubMed
7.
Li W, Xie L, Chen Z, Zhu Y, Sun Y, Miao Y, Xu Z, Han X: Cantharidin, a potent and selective PP2A inhibitor, induces an oxidative stress-independent growth inhibition of pancreatic cancer cells through G2/M cell-cycle arrest and apoptosis. Cancer Sci. 2010, 101 (5): 1226-1233. 10.1111/j.1349-7006.2010.01523.x.CrossRefPubMed
8.
Millward TA, Zolnierowicz S, Hemmings BA: Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci. 1999, 24 (5): 186-191. 10.1016/S0968-0004(99)01375-4.CrossRefPubMed
9.
Janssens V, Goris J, Van Hoof C: PP2A: the expected tumor suppressor. Curr Opin Genet Dev. 2005, 15 (1): 34-41. 10.1016/j.gde.2004.12.004.CrossRefPubMed
10.
Li W, Chen Z, Zong Y, Gong F, Zhu Y, Lv J, Zhang J, Xie L, Sun Y, Miao Y, et al: PP2A inhibitors induce apoptosis in pancreatic cancer cell line PANC-1 through persistent phosphorylation of IKKalpha and sustained activation of the NF-kappaB pathway. Cancer letters. 2011, 304 (2): 117-127. 10.1016/j.canlet.2011.02.009.CrossRefPubMed
11.
Li W, Chen Z, Gong FR, Zong Y, Chen K, Li DM, Yin H, Duan WM, Miao Y, Tao M, et al: Growth of the pancreatic cancer cell line PANC-1 is inhibited by protein phosphatase 2A inhibitors through overactivation of the c-Jun N-terminal kinase pathway. Eur J Cancer. 2011,  -Epub ahead of print
12.
Cao G, Kuriyama S, Gao J, Nakatani T, Chen Q, Yoshiji H, Zhao L, Kojima H, Dong Y, Fukui H, et al: Gene therapy for hepatocellular carcinoma based on tumour-selective suicide gene expression using the alpha-fetoprotein (AFP) enhancer and a housekeeping gene promoter. Eur J Cancer. 2001, 37 (1): 140-147. 10.1016/S0959-8049(00)00344-0.CrossRefPubMed
13.
Evans DR, Myles T, Hofsteenge J, Hemmings BA: Functional expression of human PP2Ac in yeast permits the identification of novel C-terminal and dominant-negative mutant forms. J Biol Chem. 1999, 274 (34): 24038-24046. 10.1074/jbc.274.34.24038.CrossRefPubMed
14.
Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mitchell JB: Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer research. 1987, 47 (4): 936-942.PubMed
15.
Ma T, Zhu ZG, Ji YB, Zhang Y, Yu YY, Liu BY, Yin HR, Lin YZ: Correlation of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase with sensitivity of gastrointestinal cancer cells to 5-fluorouracil and 5-fluoro-2'-deoxyuridine. World J Gastroenterol. 2004, 10 (2): 172-176.PubMedPubMedCentral
16.
Weiner MP, Costa GL, Schoettlin W, Cline J, Mathur E, Bauer JC: Site-directed mutagenesis of double-stranded DNA by the polymerase chain reaction. Gene. 1994, 151 (1–2): 119-123.CrossRefPubMed
17.
Nelson M, McClelland M: Use of DNA methyltransferase/endonuclease enzyme combinations for megabase mapping of chromosomes. Methods Enzymol. 1992, 216: 279-303.CrossRefPubMed
18.
Kita-Matsuo H, Barcova M, Prigozhina N, Salomonis N, Wei K, Jacot JG, Nelson B, Spiering S, Haverslag R, Kim C, et al: Lentiviral vectors and protocols for creation of stable hESC lines for fluorescent tracking and drug resistance selection of cardiomyocytes. PloS one. 2009, 4 (4): e5046-10.1371/journal.pone.0005046.CrossRefPubMedPubMedCentral
19.
Nakabayashi H, Hashimoto T, Miyao Y, Tjong KK, Chan J, Tamaoki T: A position-dependent silencer plays a major role in repressing alpha-fetoprotein expression in human hepatoma. Mol Cell Biol. 1991, 11 (12): 5885-5893.CrossRefPubMedPubMedCentral
20.
He TC, Zhou S, da Costa LT, Yu J, Kinzler KW, Vogelstein B: A simplified system for generating recombinant adenoviruses. Proceedings of the National Academy of Sciences of the United States of America. 1998, 95 (5): 2509-2514. 10.1073/pnas.95.5.2509.CrossRefPubMedPubMedCentral
21.
Nicoletti I, Migliorati G, Pagliacci MC, Grignani F, Riccardi C: A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods. 1991, 139 (2): 271-279. 10.1016/0022-1759(91)90198-O.CrossRefPubMed
22.
Yeh CB, Su CJ, Hwang JM, Chou MC: Therapeutic effects of cantharidin analogues without bridging ether oxygen on human hepatocellular carcinoma cells. Eur J Med Chem. 2010, 45 (9): 3981-3985. 10.1016/j.ejmech.2010.05.053.CrossRefPubMed
23.
Zheng LH, Bao YL, Wu Y, Yu CL, Meng X, Li YX: Cantharidin reverses multidrug resistance of human hepatoma HepG2/ADM cells via down-regulation of P-glycoprotein expression. Cancer letters. 2008, 272 (1): 102-109. 10.1016/j.canlet.2008.06.029.CrossRefPubMed
24.
Honkanen RE: Cantharidin, another natural toxin that inhibits the activity of serine/threonine protein phosphatases types 1 and 2A. FEBS Lett. 1993, 330 (3): 283-286. 10.1016/0014-5793(93)80889-3.CrossRefPubMed
25.
Zabner J, Wadsworth SC, Smith AE, Welsh MJ: Adenovirus-mediated generation of cAMP-stimulated Cl- transport in cystic fibrosis airway epithelia in vitro: effect of promoter and administration method. Gene Ther. 1996, 3 (5): 458-465.PubMed
26.
Fallaux FJ, Bout A, van der Velde I, van den Wollenberg DJ, Hehir KM, Keegan J, Auger C, Cramer SJ, van Ormondt H, van der Eb AJ, et al: New helper cells and matched early region 1-deleted adenovirus vectors prevent generation of replication-competent adenoviruses. Hum Gene Ther. 1998, 9 (13): 1909-1917. 10.1089/hum.1998.9.13-1909.CrossRefPubMed
27.
Regulier E, Schneider BL, Deglon N, Beuzard Y, Aebischer P: Continuous delivery of human and mouse erythropoietin in mice by genetically engineered polymer encapsulated myoblasts. Gene Ther. 1998, 5 (8): 1014-1022. 10.1038/sj.gt.3300687.CrossRefPubMed
Metadata
Title
Development of a gene therapy strategy to target hepatocellular carcinoma based inhibition of protein phosphatase 2A using the α-fetoprotein promoter enhancer and pgk promoter: an in vitro and in vivo study
Authors
Wei Li
Dao-Ming Li
Kai Chen
Zheng Chen
Yang Zong
Hong Yin
Ze-Kuan Xu
Yi Zhu
Fei-Ran Gong
Min Tao
Publication date
01-12-2012
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2012
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-12-547

Other articles of this Issue 1/2012

BMC Cancer 1/2012 Go to the issue

Research article

The risk allele of SNP rs3803662 and the mRNA level of its closest genes TOX3 and LOC643714predict adverse outcome for breast cancer patients

Research article

PCA3 noncoding RNA is involved in the control of prostate-cancer cell survival and modulates androgen receptor signaling

Research article

C-reactive protein in patients with advanced metastatic renal cell carcinoma: Usefulness in identifying patients most likely to benefit from initial nephrectomy

Research article

Deregulation of miR-100, miR-99a and miR-199b in tissues and plasma coexists with increased expression of mTOR kinase in endometrioid endometrial carcinoma

Research article

Reovirus exerts potent oncolytic effects in head and neck cancer cell lines that are independent of signalling in the EGFR pathway

Research article

The cyclin-like protein Spy1/RINGO promotes mammary transformation and is elevated in human breast cancer
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