Suppression of breast tumor growth by DNA vaccination against phosphatase of regenerating liver 3.
Phosphatase of regenerating liver (PRL)-3 is highly expressed in multiple cancers and has important roles in cancer development. Some small-molecule inhibitors and antibodies targeting PRL-3 have been recently reported to inhibit tumor growth effectively. To determine whether PRL-3-targeted DNA vaccination can induce immune response to prevent or inhibit the tumor growth, we established mouse D2F2 breast cancer cells expressing PRL-3 (D2F2/PRL-3) and control cells (D2F2/NC) with lentivirus, and constructed pVAX1-Igκ-PRL-3 plasmid (named as K-P3) as DNA vaccine to immunize BALB/c mice. We found that the K-P3 vaccine delivered by gene gun significantly prevented the growth of D2F2/PRL-3 compared with pVAX1-vector (P<0.01), but not of D2F2/NC, and improved the survival of D2F2/PRL-3-innoculated mice. Both PRL-3-targeted cytotoxic T lymphocytes (CTLs) and T-helper type 1 cell immune response (production of high levels of interferon-γ and tumor necrosis factor-α) were found to be involved in the preventive effect. Furthermore, PRL-3-targeted DNA immunization inhibited tumor growth of D2F2/PRL-3 cells in mice. We also evaluated the potential of immunization with PRL-3 protein, but no significant therapeutic or preventive effect was obtained on tumor growth. To enhance the immunity of PRL-3, we incorporated different molecular adjuvants, such as Mycobacterium tuberculosis heat-shock protein, CTL antigen 4 and M. tuberculosis T-cell stimulatory epitope (MT), into K-P3 vaccine for expressing the fusion proteins. We found that these adjuvant molecules did not significantly improve the antitumor activity of PRL-3 vaccine, but enhanced the production of PRL-3 antibodies in immunized mice. Summarily, our findings demonstrate that PRL-3-targeted DNA vaccine can generate significantly preventive and therapeutic effects on the growth of breast cancer expressing PRL-3 through the induction of cellular immune responses to PRL-3.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing, China.
J
J
Lv
C
C
Liu
H
H
Huang
L
L
Meng
B
B
Jiang
Y
Y
Cao
Z
Z
Zhou
T
T
She
L
L
Qu
S
S
Wei Song
C
C
Shou
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000276:immunology; D009363:Neoplasm Proteins / Q000235:genetics* / Q000276:immunology; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000276:immunology
D009363:Neoplasm Proteins; D019444:Vaccines, DNA; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases