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The Ideal Target Antigen for HPV Therapeutic Vaccine Development-E7

2020-12-09
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Human papillomavirus (HPV) is related to some tumors, such as cervical cancer, head and neck tumors, etc. E7 in HPV gene is the main transforming gene of the virus, and the sustained high-level expression of E7 protein is necessary for the maintenance of the malignant phenotype of tumor cells. E7 protein is a heterologous viral protein, which is a tumor-specific antigen and an ideal target antigen for cervical cancer immunotherapy. The use of tumor cell lines to construct a mouse cervical cancer model can be used as a model for detecting HPV-related tumor immunotherapy. The optimized and modified E7 gene can be obtained by gene synthesis method and named mE7. Some researchers have used DCs stimulated by pre-expression and purification of HPV mE7 protein to conduct cellular immunotherapy studies on mouse colon cancer models and found that they have a certain inhibitory effect on the tumor.

The E6 and E7 coding genes in HPV genes are the most important for cell growth stimulation. They can be expressed in highly malignant tumors and cervical cancer tissues and are HPV oncogenes. The E6 and E7 proteins encoded by E6 and E7 cause cervical epithelial cell transformation and can promote cell malignancy. For therapeutic vaccines, the research object is generally viral proteins expressed in cells. Because high-risk HPV E6 and E7 proteins are recognized transforming proteins, they are highly expressed in high-risk CIN and cervical cancer tissues, so they become a research The most target antigen.

E7 is a recognized key oncogene, and its sustained expression is necessary for the maintenance of the malignant phenotype of cervical cancer, so it is an ideal target antigen for cervical cancer therapeutic vaccines. Research on HPV therapeutic vaccines with E6 or E7 as the target antigen, and experiments on mouse cervical cancer models, some of the results are encouraging.

Research on HPV m E7 as a specific antigen for immunotherapy of cervical cancer

Culture human dendritic cells (DC) and cytokine-induced killer cells (CIK) in vitro to explore the effect of HPV mE7 protein on DC and CIK cells [1]. The method is to separate and culture DC and CIK cells in the peripheral blood of healthy people, add purified HPV mE7 protein as a stimulating factor, and detect the surface specific factors of DC and CIK cells by flow cytometry. Results The DC and CIK cells from human peripheral blood were successfully isolated and cultured. The expression of specific factors on the cell surface did not change significantly after HPV mE7 protein stimulation. Researchers have successfully established DC and CIK cell separation and culture technology. The purified HPV mE7 can be used as a specific antigen for cervical cancer immunotherapy research.

Therapeutic study of DCs stimulated by HPV mE7 on mouse cervical cancer model

The TC-1 cell line can be used to construct a mouse cervical cancer model as a model for detecting the effect of HPV-related tumor immunotherapy. Medicilon provides a variety of effective animal models according to customer needs to test the effectiveness of drugs. Experimental animals include non-human primates, dogs, mice, rats, rabbits, guinea pigs, nude mice and other types. At present, a number of effective animal tumor models have been established, and they have undergone multilateral verification and long-term practice tests.

Some researchers have also studied the killing effect of dendritic cells (DCs) stimulated by human papillomavirus (HPV) mE7 protein on cervical cancer cells in mice [2]. Establish a tumor-bearing mouse model of cervical cancer cell TC-1, isolate peripheral blood mononuclear cells and purify and culture DCs, and express the purified HPV mE7 protein with phosphate buffered saline (PBS), DCs (DCs+PBS) and previous experiments Stimulated DCs (DCs+HPV mE7) were used to immunize tumor-bearing mice, observe tumor growth in mice, and detect the in vitro lysis rate of spleen cells to TC-1 cells, IFN-γ and IL-12 in serum The expression level. Results The tumor-bearing mouse model of cervical cancer cell TC-1 was successfully constructed. DCs have a certain inhibitory effect on the growth of TC-1 cell tumors, but the stimulation of specific antigens has a limited effect on promoting DCs to kill tumor cells.

The E7 gene is an oncogene. The oncoprotein encoded by the E7 gene can regulate the cell cycle, so that the differentiated host keratinocytes are at a stage suitable for viral gene replication and amplification and late gene expression. Each oncoprotein acts on many target molecules, of which p53 and retinoblastoma inhibitory protein (pRB) are the most important. E7 eliminates cell cycle arrest by inhibiting pRB (E7 protein can reduce the stability of the retinoblastoma protein complex, allowing cells to escape the cell cycle regulation regulated by the pRB pathway). E7 is the main transforming protein. E7 competes with retinoblastoma protein (pRB) for binding to release the transcription factors E2F, E2F to activate its target cells and accelerate the cell cycle process. The “inactivation” of the two host cell tumor suppressor genes (p53, RB) increases the possibility of cell malignant transformation.

The expression level of E7 protein is low during HPV infection. In some unknown links of transformation into precancerous lesions, the expression of E7 gene increases, thereby overexpressing in the entire epithelium. HPV E7 is necessary to maintain cell transformation. It is integrated in the human genome and continuously expressed in transformed cells. It is a molecular marker of tumor cells. E7 protein is regarded as a tumor-specific antigen and is an important focus of research and development of HPV vaccines. .

[1] The effect of HPV_mE7 protein on the phenotypic characteristics of human DC and CIK cells [J].

[2] HPV mE7 stimulated DCs for the treatment of cervical cancer mouse model [J].

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