Enhanced Apoptotic Activity of a p53 Variant in Tumors Resistant to Wild-Type p53 Treatment
Isabella AtencioJenny B. AvanziniDuane E. JohnsonSaskia NeuteboomMei-Ting VaillancourtLoretta L. NielsenGerry HajianSuganto SutjiptoBarry J. SugarmanJennifer PhilopenaDiane McAllisterJosefina C. BeltranMargarita NodelmanMurali RamachandraKen N. Wills
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Abstract:
TP53 is the most commonly altered tumor-suppressor gene in cancer and is currently being tested in Phase II/III gene replacement trials. Many tumors contain wild-type TP53 sequence with elevated MDM2 protein levels, targeting p53 for degradation. These tumors are more refracto-ry to treatment with exogenous wild-type p53. Here we generate a recombinant adenovirus expressing a p53 variant, rAd-p53 (d 13–19), that is deleted for the amino acid sequence neces-sary for MDM2 binding (amino acids 13–19). We compared the apoptotic activity of rAd-p53 (d 13–19) with that of a recombinant adenovirus expressing wild-type p53 (rAd-p53) in cell lines that differ in endogenous p53 status. rAd-p53 (d 13–19) caused higher levels of apoptosis in p53 wild-type tumor lines compared with wild-type p53 treatment, as measured by annexin V-FITC staining. In p53-altered tumor lines, rAd-p53 (d 13–19) showed apoptotic activity similar to that seen with wild-type p53 treatment. In normal cells, no increase in cytopathicity was detected with rAd-p53 (d 13ndash;19) compared with wild-type p53 treatment. This variant protein displayed synergy with chemotherapeutic agents to inhibit proliferation of ovarian and breast cell lines. The p53 variant showed greater antitumor activity in an established p53 wild-type tumor com-pared with treatment with wild-type p53. The p53 variant represents a means of expanding TP53 gene therapy to tumors that are resistant to p53 treatment due to the cellular responses to wild-type p53.Keywords:
P53 protein
Wild type
P53 expression
Objective To explore the protein expression of P53 in osteosarcoma and its relationship between P53 and the three year survival rates of osteosarcoma patients.The protein expression of P53 was detected by using immunohistochemical.Methods In 53 cases of osteosarcoma proved by surgery and pathology.Results (1) There was no significant relationship between the protein expression of P53 and the three year survival rates of osteosarcoma patients.The positive expression of P53 was 13.2% (7/53).(2) A negative correlation,analyzed by logistic regression,was existed between the P53 expression and the patients′ prognoses.Conclusion There is a high death rate in osteosarcoma patients with positive protein expression of P53.
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Objective To explore the prognostic value of p53 expression in patients with colorectal cancer at different location.Methods p53 protein was detected by immunohistochemistry in tumor tissue specimens from 75 primary colorectal adenocarcinomas.Results Of 75 samples,35(46.7%) had positive expression of p53.p53 overexpression was more frequently existed in distal-located tumor than in proximal-located tumor(59.5% vs.30.3%,P0.05).There was no correlation between p53 expression and other clinicopathologial variables.Median follow-up duration was 60 months.Patients with p53-positive tumors showed a lower overall survival rate than those with p53-negative tumors(P0.05).Furthermore,in patients with distal-located colorectal cancer,p53-positive patients had significantly poor prognosis,compared with p53-negative patients(P0.01),but in patients with proximal-located colon cancer,prognosis was not different(P0.05).Conclusion The overexpression of p53 protein is influenced by the the tumor location.It may provide important prognostic information in distal-located colorectal cancer.
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瞄准：为了描绘肿瘤，压制或基因 p53 变化和研究 p53 基因变化的关联和在 cholangiocarcinoma 的 P53 蛋白质的表示。方法：36 unselected 的一个总数， cholangiocarcinoma 的冻结的样品被收集。p53 基因地位(5-8 上的前) 和 P53 蛋白质被定序自动化和免疫检验组织化学的染色，与病人的临床的参数结合了。结果：p53 基因变化在 36 中的 22 个被发现(61.1%) 病人。36 中的十九个(52.8%) 病人们为 P53 是积极的蛋白质表示。在在 P53 蛋白质的积极、否定的表示之间的区别和侵略的程度有有效差量。然而，在在变化和非变化之间的病理学的参数没有有效差量。结论：DNA 评估的 p53 基因的改变定序分析是相对精确的。当一个独立人士索引估计 cholangiocarcinoma 的预后， P53 蛋白质的表示不能行动。
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Objective To investigate the expression of p53,Bcl 2 and Ki 67 protein in cutaneous basal cell carcinoma (BCC).Methods Archival specimens of BCC had been studied by immunohistochemical technique.Results The expression rates of p53,Bcl 2 and Ki 67 protein of 33 patients with BCC were 45.45%,54.55%,36.36%,respectively.Conclusion The mutation of p53 gene may be concerned with the occur and development of BCC.
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Objective: To investigate the prognostic value of p53 expression for the epithelial ovarian carcinoma. Methods: p53 protein expression was examined by immunohistochemical method in 72 patients with epithelial ovarian carcinoma. Results: The p53 protein was less expressed in G1 and G2 groups than in G3 group. Moreover, p53 protein expression varied among different clinical stages. p53 expression in stages Ⅰ and Ⅱ was less than that of stages Ⅲ and Ⅳ. There was no significant difference between p53 expression and histological types. The p53 expression was associated with the 5-year survival rate in patients with p53 negative and p53 positive were 60. 71 % and 27. 27% respectively, the difference was significant (P0. 05). Conclusion: p53 protein expression related with the histological grade and clinical stages, but not with the histological type. p53 expression could be as a factor both in predicting prognosis of patients and anti-cancer drug resistance in epithelia ovarian cancer.
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المقدمه:- سرطان القولون والمستقيم هو أكثر أنواع السرطان شيوعا بعد سرطان الثدي في النساء وسرطان القصبات الهوائية في الذكور. المعلم السرطاني p53 هو قامع الجينات السرطانية، تقريبا نصف سرطان القولون والمستقيم يحدث في طفرة جين المعلم السرطانيp53. الهدف من الدراسة: - تحديد وتيرة ونمط التعبير المناعي لp53 في سرطان القولون والمستقيم بواسطه فحوصات المناعه النسيجيه والكيميائيه وتقيم العلاقه مع مختلف الدلالات السريريه والمرضيه. المواد والأسلوب: - ثلاثون حاله لمرضى سرطان القولون والمستقيم، تم تشخيصها في المختبرات الاهليه في بغداد / العراق خلال الفترة من كانون الثاني2015 لغايه حزيران2015. بواسطه الفحوصات المناعيه النسيجيه من ناحيه العمر ،الجنس، حجم الورم, موقع الورم ، عدد الغدد الليمفاوية ، تمايز الورم ومراحل انتشار المرض عن طريق فايلات المرضى(المقاطع النسيجيه المصبغه بصبغه اليموتوكسلين والايوسين وصبغه البروتين المناعي لp53). النتائج:- تسعة عشر (63.3٪) من الحالات ذكورا، و 11 (36.7٪) من الحالات إناثا، بفئات عمريه تتراوح من (89-39) سنة بمتوسط عمر 56.5 عاما .عشر حالات (33.3٪) تقع في بدايه الامعاء الغليظه، و3 (10٪) حالات تقع في القولون الصاعد و 8 (26.7٪) حالات تقع في القولون النازل والملتوي و6 (20٪) حالات تقع في المستقيم. تشريحيا درجات الورم تتراوح بين معتدلة في 27 (90٪) من الحالات، وصعبه التميز في 3 (10٪) من الحالات. وفيما يتعلق بمراحل المرض كانت 2 (6.7٪) من الحالات كانت في المرحله الثانيه،و24( (80% في المرحله الثالثه ، و4 (13.3٪) من الحالات في المرحله الرابعه. اما اصابه العقدة الليمفاوية فوجد14 (46.7٪) من الحالات، والانبثاث البعيدة في 3 (10٪) من الحالات. كان التعبير المناعي لبروتين p53 في 11 (36.7٪) من الحالات، وزعت على النحو التالي: - ضعيفه في 1(3.3٪) حالة ، ومتوسطه في 3 (10٪) حالات وسرطانيه في 7 (23.4٪) من الحالات. الاستنتاج:-. لم يكن هناك ارتباط بين التعبير لبروتين p53 والعمر ،الجنس، التمايز النسيجي، الموقع، اصابه الغدد الليمفاوية ومرحلة الورم.
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Objective:To study the relationship and expression of bcl-2 and p53 protein in gastric carcinoma. Methods:The bcl-2 and p53 proteins in all the cases were detected by immunohistochemical methods.Results:The expression of bcl-2 in gastric carcinoma was higher than that in chronic gastric diseases, but no significantly(P0. 05). The expression of p53 in gastric carcinoma was higher than that in chronic gastric diseases(P0. 05). There was no significant correlation between expressionof bcl-2 and p53(P0.05). Conclusions: Expression of bcl-2 and p53 was in different period of the formation and development of gastric carcinoma.
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大腸癌81例, 大腸腺腫36例, 正常大腸粘膜42例について, 抗 p53 モノクローナル抗体(PAb-1801)を用いた免疫組織化学染色を行い, p53 の異常発現を検討し, また大腸癌病変中52例については, DNA ploidy の検索も行った. p53の異常発現は, 大腸癌44例(54.3%), 大腸腺腫4例(11.1%)にみられ, 正常大腸粘膜にはみられなかった, 大腸癌では, 大腸腺腫(p<0.01), 正常大腸粘膜 (p<0.01) のいずれに比しても有意に p53 の発現頻度が高く, 大腸腺腫でも正常大腸粘膜に比して p53 の発現頻度は有意に高かった (p<0.05). 大腸癌の臨床病理学的所見と p53 異常発現との関係では, 肝転移とのみ有意に (p<0.05) 相関したが, 他の因子との相関を認めなかった. DNA aneuploidy と P53 異常発現の間にも相関はなかった. このことから, p53 の異常所見は, 大腸腫瘍発生段階の後期に関与するが, その後の進展には関与するところが少ないと考えられた.
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AIM: To study the correlation between Pixuzheng of colorectal carcinoma and the expression of p53, Bcl 2 and Bax. METHODS: Sixty one patients with advanced poorly differentiated adenocarcinomas were divided into Pixuzheng and non pixuzheng groups according to syndrome differentiation of TCM. The semiquantitative scores of the syndrome of each patient were counted. And there was a control group of 20 healthy volunteers without lesion of colonic mucosa. Immunohistochemistry S P was used to detect the expression of p53, Bcl 2 and Bax proteins. RESULTS: The positivity rate and level of expression of p53 and Bcl 2 in Pixuzheng group were significantly higher than those in non pixuzheng group ( P 0.05). There was no significant difference in the positivity rate of the expression of Bax between Pixuzheng and non pixuzheng groups ( P 0.05). There was significant correlation between the expression of p53 or Bcl 2 protein and scores of Pixuzheng ( P 0.01). There was no significant correlation between the expression of Bax and scores of Pixuzheng ( P 0.05), and between the expression of p53, Bcl 2 or Bax protein and the scores of non pixuzheng ( P 0.05). CONCLUSION: There is correlation between Pixuzheng of colorectal carcinoma and abnormal expression of p53 and Bcl 2.
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