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Study on Therapy of Transplanted Prostatic Cancer in Mouse Models with Attenuated Salmonella Typhimurium Carrying siRNA-STAT3 Expressing Plasmid

Author: LiuXiDong
Tutor: ZhouQingWei
School: Jilin University
Course: Biomedical Engineering
Keywords: prostatic cancer attenuated salmonella STAT3 RNAi
CLC: R737.25
Type: Master's thesis
Year: 2009
Downloads: 57
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Abstract


Prostatic cancer is one of malignant tumors in Europe and America countries. In 1998,39.2 thousand of people died of this cancer, with the amount of death ranking as Number two among all of male carcinomas. During the recent two decades, With the aging of population and the changing of life style and diet, the incidence of prostatic cancer tended to increase gradually. the review investigation towards 358 patients of prostatic cancer in 8 big hospitals of Changchun city since the year 1986 which was made by prevention and treatment center of prostatic cancer in hospital of China-Japan friendship has showed that the diagnosis number of prostatic cancer during the year 1999-2001 increased by 4.6 times as much as that during the year 1986-1988.What’s more, the number of middle and advanced prostatic cancer accounted for 71% of patients. We can use radical surgery and radiation therapy for the treatment of early prostatic cancer, while nearly one third of the patients will have a relapse and become the independent Androgenic prostatic cancer after 18 months’treatment. Traditional treatments, such as radiotherapy, chemotherapy and surgery can’t solve both tumor metastasis and transformation from hormone -dependent to hormone- independent. Therefore, many researchers presume that solving the problem may depend on the newly emerging biotherapy.Signal Transducer and Activator of Transcription (STAT) family are kind of proteins which exist in kytoplasm and then shift into intranuclear for combining with DNA if activated. They own the double function of signal transduction and transcriptional control. STAT3, an important member of the family, is expressed highly in many human malignant tumors and closely associated with tumor differentiation extent, tumor metastasis and patient prognosis. Because of these, it can be considered as an indication of prognosis and a new target for treatment, making it hopeful to become one of the new tumor markers. Inhibitors of STAT3 indicated that they had a strong function of suppressing the tumor cells’growth in vitro and the animal model. It will open up a new path for the treatment of malignant tumors due to the abnormal expressions of STAT3 to pick up strong and specific inhibitors of STAT3.The main hindrance which exists in gene therapy of tumors is that it is difficult to transfer Antioncogenes to tumor tissues specifically. Now Exploring a gene transfer system of high performance and target is a critical and emergent problem to solve for the treatment of malignant tumors. Recent studies showed that facultative anaerobes, such as salmonella, were inclined to gather together and reproduce at the tumor tissue areas of hypoxia and cellular necrosis. Especially, auxotrophic bacteria exhibited high selectivity towards tumor tissues. And the generations of bacterial Amplification in tumor tissues were much more than those in normal tissues at the same time, which made attenuated saimonella become possible as a new vector of antitumor and tumor targeted therapy.Objective:Observe therapeutic efficacy of attenuated saimonella carrying the siRNA-Stat3 plasmid towards transplanted prostatic cancers of mouse.Methods:we built prostatic transplanted cancer models of mouse and made an randomization, then injected attenuated salmonella with transformed plasmid of siRNA-STAT3 into local bodies of mouse models constructed successfully. Next we Observed the general status of the mouse and recorded the changing volumes of tumors. Then the expressions of mRNA and protein of STAT3 and its downstream genes such as Bcl-2, c-Myc, HiF1, cyclinD1 were analysed. Finally we Observed the distributions of microbial population by means of planking, morphological changes of tumors with staining of HE and detected protein expressions of STAT3, HiF1 and PCNA with immunohistochemistry, Apoptosis of tumorous cells with flow cytometry.Results:(1) prostatic transplanted cancer models of mouse were made successfully,and the group treated with salmonella of siRNA-STAT3 plasmid showed that the growth of tumors was suppressed obviously and the weight of tumors was lessened.(2) Detecting the distributions of microbial population by planking showed that attenuated salmonella had the characteristics of being tumor-addicted and alive for long in the tumor tissues and that the distributions of microbial population in liver were less than that in tumors,lungs thirdly,spleen the least.(3) Detections of flow cytometry revealed that early apoptotic rate of the cancer group treated with pGC-Si-STAT3, that of the cancer group treated with pGC-Si-Scramble and that of group mock reached 29.1%, 14.7% and 8.5% respectively.(4) The mRNA and protein expressions of Stat3 in the tumor tissues treated with pGC-Si-STAT3 decreased greatly. mRNA expressions of downstream genes, such as Bcl-2, c-Myc were inhibited in a different degree, and the protein expressions of HiF1, cyclinD1 were just the same.(5) immunohistochemistry showed that the expressions of STAT3, HiF1 and PCNA in the tumor tissues treated with pGC-Si-STAT3 were down regulated.Conclusion:Regulating expressions of STAT3 to induce apoptosis by means of plasmid of siRNA-STAT3 with the transporter of attenuated salmonella suppressed the transplanted prostatic cancers of mouse.

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CLC: > Medicine, health > Oncology > Genitourinary tumors > Male genitalia tumors > Prostate cancer
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