Inhibitory effects on liver tumors of BALB/c mice bearing H22 cells by immunization with recombinant GnRH immunogen coupled to heat shock protein 65 (2023)


Volume 25, numbers 39-40,

28 september 2007

, pages 6911-6921

Author links open the overlay panel, , , ,


In the following study, we prepared a double-stranded miniprotein where each strand contains three linear repeats of its own gonadotropin-releasing hormone (GnRH) peptide3), ofjoint regionhumanIgG1(hinge) and T helper epitope of measlesprotein viruses(MVP). di-GnRH3hinge MVP miniprotein was conjugated to a purified recombinantheat shock protein 65(Hsp65) fromMycobacterium bovisand used to immunize BALB/cmicejacket withsubcutaneous injectionBacillus Calmette-Guerin (BCG) in the absence of adjuvants. After successfully producing anti-GnRH antibodies, mice were inoculated with H22 cells assolide tumor. The results showed that serum testosterone levels decreased significantly after GnRH was inhibited with anti-GnRH antibodies (P<0.01) itesticlereduced weight (P<0,05) uGnRH3hinge-MVP-Hsp65-immunized mice. Mean tumor weight in GnRH-treated mice3hinge MVP Hsp65 was significantly lower than in mice treated with saline alone (neutral control,P<0.001), or less than in Hsp65-treated mice (negative control,P<0.005). The data presented here showed that GnRH3hinge-MVP-Hsp65 could significantly attenuate liver tumor progression in mice transplanted with H22 cells, and could developpalliative treatmentpatients with hepatocellular carcinoma (HCC) in the future.


Hepatocellular carcinoma (HCC) is the fifth most common malignant tumor in the world. In China, it is the second leading cause of cancer death in men and the third in women [1], [2]. The pathogenesis of HCC is still poorly understood, and what we do know is that some factors are associated with an increased risk of developing cancer. Several risk factors are believed to play a role in HCC [3]. Epidemiological studies on HCC show a clear disadvantage of the male gender. For example, in Asian countries, the ratio of men to women ranges from 2.4 to 4.3 [4]. Not only do men develop HCC, they also die more easily than women: in fact, the prognosis for the disease is more malignant in men than in women, and men have poorer survival and more disease recurrence after treatment [3]. Due to their marked male predominance, androgens have been investigated as potential factors that can induce or at least promote liver carcinogenesis, and this hypothesis is also supported by the ability of androgens to induce liver neoplasms in experimental models [5], [6], [7] . Elevated levels of serum testosterone (T) and T to estradiol (E2) ratio has been proposed to predict an increased risk of HCC in cirrhotic male patients [8]. On the other hand, estrogens are involved in the regulation of hepatocyte proliferation and estrogen receptors (ER) are present in livers with cirrhosis and HCC. In fact, after partial hepatectomy in humans, there is a 'feminization' of the liver microenvironment [9]. As a result, both the presence of male sex hormones and the feminizing effect caused by cirrhosis have been blamed, at least in part, for the development of HCC. It has therefore been suggested that changes in sex hormones may play a role in liver carcinogenesis [10]. Palliative treatment of liver cancer patients with antihormones has been widely used in the past. However, the molecular mechanism underlying the action of sex steroids on hepatocarcinoma cells has not yet been fully elucidated, nor have endocrine discriminants been satisfactorily evaluated for adequate characterization of liver cancer. Recently, both the androgen receptor (AR) protein and its mRNA have been found to be elevated in liver tumors from male individuals [11], which are thought to be involved in male predominance. Many researchers have reported that sex hormones can cause DNA alteration and growth factor changes in liver cells [12].

Gonadotropin-releasing hormone (GnRH) is an endogenous hormone containing 10 amino acid residues. GnRH plays a key role in the regulation of the pituitary-gonadal axis: it selectively stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary to promote ovarian follicular maturation and spermatogenesis [13]. This feature has attracted widespread attention due to its enormous potential as an anti-hormone reagent. While GnRH analogs have been used clinically to treat a number of hormone-dependent diseases, they often require large, toxic, and expensive doses of the drug to be administered. Induction of an immune response against GnRH could therefore prove to be less toxic and less expensive in the treatment of such hormone-related disorders [14]. In our lab, we successfully prepared a synthetic mini-protein consisting of three GnRH repeats (GnRH3), a T helper epitope of the measles virus protein (MVP) and the hinge region of human IgG1 (hinge), called GnRH3-hinges-MVP. Double-chain miniprotein (di-GnRH3hinge MVP) is obtained by oxidation of GnRH3-hinges-MVP. GnRH miniprotein3hinge MVP successfully induced an anti-GnRH immune response in rats in the presence of Freund's adjuvant. However, Freund's adjuvant is not allowed in the human body. To address this issue, we investigated the use of di-GnRH3hinge MVP conjugated to heat shock protein 65 (Hsp65) is derived fromMycobacterium bovisBacillus Calmette-Guerin (M. bovisBCG) to induce anti-GnRH antibodies in male BALB/c mice.

In addition, there is ample evidence for the expression of GnRH and its receptors in tissues outside the pituitary gland, particularly in a range of tumors not only of reproductive origin, including breast [15], prostate [16], ovary [17] and endometrium [ 1]. 18], but also non-reproductive tissues of liver [19], kidney [20], pancreas [21]. There is increasing research on the existence of GnRH and its binding sites in human hepatocarcinoma tissue and its cell lines [22], [23], [24]. Although the function of the GnRH autocrine system in liver tumors has not been elucidated, it is believed that GnRH plays an important role in the promotion and progression of liver tumors and will become the target of therapeutic approaches against HCC. Based on this, it is speculated that the biological effect of GnRH and GnRH analogues on liver tumors may lie in two aspects: one blocks the secretion of sex hormones by inhibiting the function of the pituitary-gonadal axis, the other causes a specific signal by the direct activation of GnRH binding sites anchored on the surface of hepatocarcinoma cells. Among the various approaches explored to control GnRH activity or treat GnRH-related diseases, active immunization using peptide-based vaccines has gained wide acceptance. The aim of this study was to confirm the effect of recombinant peptide vaccine against GnRH on H22 liver tumor in male BALB/c mice.

Fragments of sections

Cell line

The murine hepatoma cell line H22 was kindly provided by the Shanghai Institute of Materia Medica, CAS of mouse ascites, which were heterogeneous cells with a higher declination of spreading through lymphatic vessels.


Male BALB/c mice, 4-5 weeks old and weighing 15-20 g, free of specific pathogens, were obtained from the Laboratory Animal Center of the Shanghai Institute of Biological Sciences, CAS, and housed in a laminar airflow chamber under pathogen-free conditions according to schedule 12 hours light/12 hours dark. Theirs

GnRH production3hinge-MVP-Hsp65

To increase GnRH production3hinge MVP miniprotein, we select the C-terminal sequenceL. asparaginaza(ansB-C) originates from the chromosomeE coliBL21 as remainder. The ansB-C DNA fragment and an acid-labeled asparagine-proline linker (Asp-Pro) were placed at the 3' end of the T7 Φ10 promoter in the expression vector pET-28a (Novagen), designated pED. The DNA sequence encoding GnRH joint MVP obtained by double primer PCR was inserted into both ends of the pED (BamHI at the 5' end and


In previous studies, we found that GnRH3hinge MVP miniprotein in Freund's adjuvant elicited a marked anti-GnRH response in both male and female rats. Although Freund's adjuvant is capable of enhancing the immune response against poorly immunogenic epitopes, it cannot be used in the human body due to its toxicity. Recent reports indicate that mycobacterial heat shock protein 65 kDa (Hsp65) shows strong immunogenicity and contains strong T cell epitopes. Hsp65 can be used so easily and safely


This work was supported by the Committee of the National Natural Science Foundation of China (Grant No. 30500458).


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    • Preparation of a peptide vaccine against GnRH by an asparaginase-based bioprocess system

      2010, Vaccine

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      Several strategies, such as linear alignment of haptens, use of powerful adjuvants, retro-inverso strategies, and fusion or conjugation with defined T helper epitopes and/or carrier proteins, have been shown to be useful in eliciting strong immune responses [25-27]. Our previous study also proved these concepts [17,25,28,29]. Since the conventional chemical synthesis of polypeptides such as GhMNR is very time consuming, environmentally unfriendly and expensive, genetic engineering has become an attractive alternative method for the production of these peptide vaccines.

      GnRH is a promising target in hormone-dependent cancer immunotherapy. In our previous study, we used a peptide vaccine GhM (GnRH3hinge MVP) using an asparaginase-based bioprocess system. Active immunization with GhM in the presence of CFA/IFA induced a strong humoral response. In this study, the high affinity NRLLLTG motif for the nanoparticle carrier VLP HBcΔ-SBD was fused to the C-terminus of GhM to create a novel peptide vaccine GhMNR (GnRH3hinges-MVP-NRLLLTG). The ansB-C-GhMNR fusion protein is controlled by the strong T7lac promoter and efficiently expressed as inclusion bodies after lactose induction and then purified by cell disruption, washing and cold ethanol fractionation. After 72 hours of hydrolysis, GhMNR was released from the ansB-C fusion partner and purified by CM52 cation exchange chromatography. These results suggest that the bioprocess system is suitable for large-scale expression and purification of the GhMNR peptide vaccine and even some other proteins or peptides that may be important for industrial or laboratory purposes.

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      2010, The Science of Animal Reproduction

      Immunization with recombinant maltose binding protein gonadotropin-releasing hormone (MBP-GnRH6) altered both testicular development and pituitary GnRH receptor (GnRHR) gene transcription in boars. Scrotal measurements and blood samples were taken at 4 week intervals after immunization at 9 weeks of age. Concentrations of testosterone and anti-GnRH antibodies in serum were determined by radioimmunoassay and enzyme immunoassay. The results showed that active immunization with MBP-GnRH6 increases the serum concentration of anti-GnRH antibodies (P<0.05) and decreased serum testosterone concentration (P<0.05) compared to MBP controls. At 25 weeks of age, the boars were sacrificed and the testes were evaluated histologically. Testis development was suppressed in MBP-GnRH6 immunized animals compared to MBP immunized boars. MBP-GnRH6 immunized pigs showed grasping behavior 4 weeks later than MBP immunized boars. No mature spermatozoa were observed in animals immunized with MBP-GnRH6. Quantitative real-time PCR analysis found that the amount of GnRHR mRNA in pituitary tissue was significantly lower in MBP-GnRH6-immunized animals than in controls (P<0.05). These data demonstrate that recombinant MBP-GnRH6 was effective in immunocastration of boars.

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      Mucosal administration of the autoantigen HSP65 can induce an anti-inflammatory immune response and reduce organ-specific inflammation and disease in various models of autoimmunity, such as arthritis and atherosclerosis. We were interested in whether HSP65 can serve as an immunogenic carrier for the diabetogenic peptide P277 and also induce an anti-inflammatory immune response in NOD mice by mucosal administration. Thus, the dual functions of HSP65 and P277 against type 1 diabetes will be obtained. To test this hypothesis, we investigated the effect of intranasal vaccination with P277 tandem repeat sequences carried by HSP65 in the absence of adjuvant on autoimmune diabetes in NOD mice. We found a significant reduction in the incidence of diabetes, inhibition of insulitis, reduction in the secretion of isotype IgG2a antibodies against P277 and pro-inflammatory cytokines IFN-γ and IL-2, increase in subclass IgG1, IgG2b antibodies against P277 and anti-inflammatory cytokines IL-10 and IL-4 secretion, and reduced proliferation upon nasal application of the fusion protein HSP65-6×P277. Our results indicate that HSP65 may serve as a particularly beneficial carrier for P277-based vaccines, and mucosal delivery may represent a therapeutic approach for the treatment of type 1 diabetes.

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      After washing four times with TTBS, the protein bands were developed for several minutes at room temperature with TBS containing 3,3'-diaminobenzidine (DAB) and H 2 O 2 . Anti-GnRH antibody titers in immunized animals were detected by enzyme-linked immunosorbent assay (ELISA) as previously described [35]. Briefly, 96-well flat bottom ELISA plates (Costar, USA) were coated with 100 μl/well of 0.1 mg/ml VEGF-GnRH fusion proteins in 0.1 mM carbonate-bicarbonate buffer and left overnight at 4 ° C held.

      The core protein (HBc) of the hepatitis B virus has been shown to be an attractive carrier for foreign epitopes and can display green fluorescent protein (GFP) on its surface. The structure of the substrate binding domain of DnaK [DnaK (394-504 aa), DnaK SBD] is similar to GFP, so we reasoned that the DnaK SBD could also be tolerated. Electron microscopic observations suggest that chimeric proteins containing truncated HBc (HBcΔ) and the DnaK SBD could self-assemble into virus-like particles (VLPs). Subsequently, availability of DnaK SBD and adjuvantity of VLP HBcΔ-SBD were demonstrated using two recombinant peptide vaccines against gonadotropin-releasing hormone (GnRH), GhM and GhMNR. The latter additionally carries the NRLLLTG peptide motif known to bind to DnaK and the DnaK SBD. The combination of VLP HBcA-SBD and GhMNR elicited stronger humoral responses and caused further testicular atrophy than the combination of VLP HBcA and GhMNR or VLP HBcA-SBD and GhM in Balb/c mice. These findings indicate that VLP HBcA-SBD could serve as an excellent carrier for GhMNR and some other peptide vaccines.

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