DEAR EDITOR,Despite the generally increased cancer risk in large,long-lived organisms,cetaceans,among the largest and longest-living mammals,appear to possess a counteracting mechanism.Nevertheless,the genetic basis u...DEAR EDITOR,Despite the generally increased cancer risk in large,long-lived organisms,cetaceans,among the largest and longest-living mammals,appear to possess a counteracting mechanism.Nevertheless,the genetic basis underlying this mechanism remains poorly understood.The p53 pathway serves as an ideal target for studying the mechanisms behind cancer resistance,as most cancer types have evolved strategies to circumvent its suppressive functions.展开更多
BACKGROUND: It is of significance for single nucleotide polymorphisms (SNPs), a difference of rank, which exists widely in biology, genetics and other fields. OBJECTIVE: To detect polymorphism sites in exon-4 of p...BACKGROUND: It is of significance for single nucleotide polymorphisms (SNPs), a difference of rank, which exists widely in biology, genetics and other fields. OBJECTIVE: To detect polymorphism sites in exon-4 of p53 gene, promotor of Fas gene and intron-7 of Fas gene of healthy people in Han nationality in Zhejiang province. DESIGN: Simple random sampling. SETTING: Department of Surgery of the 118 Hospital of Chinese PLA.PARTICIPANTS: A total of 80 healthy people in Han nationality were selected from hospitals in Zhejiang province from August 2005 to January 2006. There were 43 males and 37 females aged from 3 to 78 years with the mean age of 39.5 years, and all subjects were consent. DNA which was used in genetic analysis was selected from peripheral venous blood of all subjects and maintained at -20℃.METHODS: Polymorphism sites in exon-4 of p53 gene, promotor of Fas gene and intron-7 of Fas gene were detected with directly DNA sequencing technique. MAIN OUTCOME MEASURES : Polymorphism sites in exon-4 of p53 gene, promotor of Fas gene and intron-7 of Fas gene of healthy people in Han nationality in Zhejiang province. RESULTS: A total of 80 samples were involved in the final analysis. SNPs sites were found at the 119^th base of exon-4 of p53 gene (the 72^nd codon of p53 gene), the 670^th base of upper start codon in promotor of Fas gene (Fas-670), and the 995^th base of intron-7 of Fas gene, especially SNPs in the 995^th base of intron-7 pf Fas gene, i.e. C→A transversion, was a new site.CONCLUSION : One unknown SNPs site is discovered in intron-7 of Fas gene of people in Han nationality in Zhejiang province. This study also proves that the 72^nd codon exists in p53 gene and the -670 polymorphism site exists in promotor of Fas gene.展开更多
AIM: To investigate the possible roles of p53 and C-mycgenes in the primary hepatocellular carcinogenesis and therelationship between the liver hyperplastic nodule(LHN) andhepatocellular carcinoma(HCC).METHODS: The ex...AIM: To investigate the possible roles of p53 and C-mycgenes in the primary hepatocellular carcinogenesis and therelationship between the liver hyperplastic nodule(LHN) andhepatocellular carcinoma(HCC).METHODS: The expression of p53 and C-myc genes wasdetected immunohist-ochemically in 73 and 60 cases of HCCand pericarcinomatous tissues, respectively .RESULTS: The positive expression of p53 in HCC wassignificantly higher than that in pericarcinomatous tissues(P<0.05). In pericarcinomatous tissues, the p53 expressionwas observed only in LHN, but not in liver cirrhosis (LC) andnormal liver tissues. The positive expression rate of C-mycin HCC or LHN was significantly higher than that in LC ornormal liver tissues (P<0.05 and P<0.01), however, nosignificant difference was found between HCC and LHN(P>0.05). The positive expression rate of p53 and C-myc inHCC was correlated with the histological differentiation, thatin the poorly differentiated was significantly higher than thatin well differentiated samples (P<0.05).CONCLUSION: The overexpression of p53 and C-myc genesmight play a role in the carcinogenesis of HCC; And LHNseems a preneoplastic lesion related to hepatocarcinogenesis;No evidence supports that LC contribute directly to thehepatocarcinogenesis.展开更多
AIM: This study investigated the anti-cancer effect ofcombined quercetin and a recombinant adenovirus vectorexpressing the human p53, GM-CSF and B7-1 genes(designated BB-102) on human hepatocellular carcinoma(HCC) cel...AIM: This study investigated the anti-cancer effect ofcombined quercetin and a recombinant adenovirus vectorexpressing the human p53, GM-CSF and B7-1 genes(designated BB-102) on human hepatocellular carcinoma(HCC) cell lines in vitro.METHODS: The sensitivity of HCC cells to anticancer agentswas evaluated by 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The viability of cells infectedwith BB-102 was determined by trypan blue exclusion. Theexpression levels of human wild-type p53, GM-CSF and B7-1genes were determined by Western blot, enzyme-linkedimmunosorbent assay (ELISA) and flow cytometric analysis,respectively. The apoptosis of BB-102-infected or quercetin-treated HCC cells was detected by terminal deoxynucleotidyltransferase (TdT) assay or DNA ladder electrophoresis.RESULTS: Quercetin was found to suppress proliferation ofhuman HCC cell lines BEL-7402, HUH-7 and HLE, with peaksuppression at 50 μmol/L quercetin. BB-102 infection wasalso found to significantly suppress proliferation of HCC celllines. The apoptosis of BB-102-infected HCC cells was greaterin HLE and HUH-7 cells than in BEL-7402 cells. Quercetin didnot affect the expression of the three exogenous genes inBB-102-infected HCC cells (P>0.05), but it was found to furtherdecrease proliferation and promote apoptosis of BB-102-infected HCC cells.CONCLUSION: BB-102 and quercetin synergeticallysuppress HCC cell proliferation and induce HCC cell apoptosis,suggesting a possible use as a combined anti-cancer agent.展开更多
AIM: To verify the effectiveness of denaturing highperformance liquid chromatography (DHPLC) in detecting somatic mutation of p53 gene in gastric carcinoma tissues.The superiority of this method has been proved in the...AIM: To verify the effectiveness of denaturing highperformance liquid chromatography (DHPLC) in detecting somatic mutation of p53 gene in gastric carcinoma tissues.The superiority of this method has been proved in the detection of germline mutations, but it was not very affirmative with respect to somatic mutations in tumor specimens. ST7 gene, a candidate tumor suppressor gene identified recently at human chromosome 7q31.1, was also detected because LOH at this site has also been widely reported in stomach cancer.METHODS: DNA was extracted from 39 cases of surgical gastric carcinoma specimen and their correspondent normal mucosa. Seven fragments spanning the 11 exons were used to detect the mutation of p53 gene and the four exons reported to have mutations in ST7 gene were amplified by PCR and directly analyzed by DHPLC without mixing with wild-type allele.RESULTS: In the analysis of p53 gene mutation, 9 aberrant DHPLC chromatographies were found in tumor tissues, while their normal-adjacent counterparts running in parallel showed a normal shape. Subsequent sequencing revealed nine sequence variations, 1 polymorphism and 8 mutations including 3 mutations not reported before. The mutation rate of p53 gene (21%) was consistent with that previously reported. Furthermore, no additional aberrant chromatography was found when wild-type DNA was added into the DNA of other 30 tumor samples that showed normal shapes previously. The positivity of p53 mutations was significantly higher in intestinal-type carcinomas (40 %) than that in diffuse-type (8.33 %) carcinomas of the stomach. No mutation of ST7 gene was found.CONCLUSION: DHPLC is a very convenient method for the detection of somatic mutations in gastric carcinoma. The amount of wild type alleles supplied by the non-tumorous cells in gastric tumor specimens is enough to form heteroduplex with mutant alleles for DHPLC detection. ST7 gene may not be the target gene of inactivation at 7q31 site in gastric carcinoma.展开更多
AIM: To determine bhe accuracy of p53 gene mutations predicted by overexpression of p53 protein immunohistochemically,and to investigate the co-mutation of p53 and K-ras genes in rectal cancer and its effect on promot...AIM: To determine bhe accuracy of p53 gene mutations predicted by overexpression of p53 protein immunohistochemically,and to investigate the co-mutation of p53 and K-ras genes in rectal cancer and its effect on promoting malignant biologic behaviors of tumors.METHODS: Ninety-seven specimens of rectal cancer were surgically resected in our hospital from August 1996 to October 1997. The hot mutation areas of p53 gene (in exons 5-8) and K-rasgene (in codon 5/12 and 13) were detected with polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), and overexpression of p53 protein was detected with immunohistochemistry (IHC) in the 97 specimens of rectal cancer. Correlation between gene mutations and tumor clinicopathologic factors was studied, and survival analysis was penfomed as well.RESULTS: There were 36 cases of p53 gene mutations in 61 p53 protein positive cases, and 21 cases of p53 gene non-mutation in 36 p53 protein negative cases respectively.The coincidence rate of p53 gene mutation by IHC method with PCR-SSCP method was 58.8% (57/97). The mutation rate of p53 gene was 52.6% (51/97), while K-ras gene mutation was observed in codons 12 and 13 in 61 cases with a mutation rate of 62.9% (61/97). Single gene mutation of p53 or K-raswas found in 32 cases. Both p53 and K-ras gene mutation were found in 48 cases. Statistical analysis showed that p53 and K-ras gene mutations were not related to the dinicopathologic factors, including tumor size, gross tumor type, histological dassification, differentiation, invasion to intestinal veins, lymphatics and nerves, invasive depth to.wall, lymph node metastasis, and Dukes' stages (P>0.05).The survival in patients with no gene mutation, single gene mutation and both gene mutations were similar (P>0.05).CONCLUSION: IHC has a certain false positive and false negative rate in detecting p53 gene mutations. Malignant biological behaviours of rectal cancer are not enhanced by p53 and K-rasgene mutations. Co-mutation of p53 and K-ras gene has neither synergic carcinogenesis-promoting effect,nor prognostic effect on rectal cancer.展开更多
Objective: Polycystic kidney disease(PKD) is the major cause of kidney failure and mortality in humans. It has always been suspected that the development of cystic kidney disease shares features with tumorigenesis, al...Objective: Polycystic kidney disease(PKD) is the major cause of kidney failure and mortality in humans. It has always been suspected that the development of cystic kidney disease shares features with tumorigenesis, although the evidence is unclear.Methods: We crossed p53 mutant mice(p53N236S, p53S) with Werner syndrome mice and analyzed the pathological phenotypes.The RNA-seq, ss GSEA analysis, and real-time PCR were performed to dissect the gene signatures involved in the development of disease phenotypes.Results: We found enlarged kidneys with fluid-filled cysts in offspring mice with a genotype of G3mTerc^(-/-)WRN^(-/-)p53^(S/S)(G3TM).Pathology analysis confirmed the occurrence of PKD, and it was highly correlated with the incidence of tumorigenesis. RNA-seq data revealed the gene signatures involved in PKD development, and demonstrated that PKD and tumorigenesis shared common pathways, including complement pathways, lipid metabolism, mitochondria energy homeostasis and others. Interestingly, this G3TM PKD and the classical PKD1/2 deficient PKD shared common pathways, possibly because the mutant p53S could regulate the expression levels of PKD1/2, Pkhd1, and Hnf1b.Conclusions: We established a dual mouse model for PKD and tumorigenesis derived from abnormal cellular proliferation and telomere dysfunction. The innovative point of our study is to report PKD occurring in conjunction with tumorigenesis. The gene signatures revealed might shed new light on the pathogenesis of PKD, and provide new molecular biomarkers for clinical diagnosis and prognosis.展开更多
Objective:To study the role of the mutations of p53, APC and K-ras genes in 47 cases of 3 types of intestinal metaplasia (IM) of gastric mucosa. Methods:In 47 cases of IM, exons 5- 8 of p53 and exons 15 of APC were ex...Objective:To study the role of the mutations of p53, APC and K-ras genes in 47 cases of 3 types of intestinal metaplasia (IM) of gastric mucosa. Methods:In 47 cases of IM, exons 5- 8 of p53 and exons 15 of APC were examined with PCR-SSCP and codon 12 of K-ras with PCR-RFLP to detect the existence of any mutations of these structures. Results:Muta- tions of p53, APC and K-ras were found in 29.8% (14/47),6.4% (3/47) and 6.4% (3/47) respectively in our series of patients who consisted of 33 with types I and II and 14 with type III of IM. The mutation rate of p53 was far higher in patients with type III IM (57.1%,8/14) than in those with types I and II IM(18.2%,6/33)(P <0.05). Though the mutation rate of APC and K-ras was also higher in the patients with type III IM than in those with types I and II IM, it was of no statistical significance (P >0.05). In one case of type III IM, mutation of both p53 and K-ras was found. Conclusion: The molecular changes of 3 types of IM are different. The mutation of p53 may be closely related to carcinogenesis in cases of type III IM and it serve as a sign for the early diagnosis of gastric carcinoma.展开更多
p53蛋白是人体内十分重要的肿瘤抑制因子,通过调节细胞周期阻滞、诱导细胞凋亡等作用发挥肿瘤抑制功能。突变后的p53蛋白不仅具有显性负性效应(dominant negative effect,DN)抑制野生型p53蛋白功能,而且还通过功能获得性效应(gain of fu...p53蛋白是人体内十分重要的肿瘤抑制因子,通过调节细胞周期阻滞、诱导细胞凋亡等作用发挥肿瘤抑制功能。突变后的p53蛋白不仅具有显性负性效应(dominant negative effect,DN)抑制野生型p53蛋白功能,而且还通过功能获得性效应(gain of function,GOF)调节细胞代谢、侵袭、迁移等方式促进肿瘤的发生。p53蛋白在超过50%的肿瘤组织中发生突变,是肿瘤细胞区别于正常细胞的一个特异性药物靶点。因此,针对突变p53蛋白开发新型抗癌药物一直是研究的热点。长期以来,由于突变p53蛋白表面较为光滑,缺乏药物结合口袋,使其被认为是一个不可成药的靶点。随着高通量筛选技术的发展以及对突变p53蛋白结构的深入了解,许多靶向突变p53蛋白的小分子化合物被报道并在体外展现出较好的抗肿瘤活性,多款基于突变p53蛋白研发的化合物已经进入临床试验阶段。本文就靶向p53蛋白治疗肿瘤的直接和间接策略进行综述,重点针对突变p53蛋白重激活剂与降解突变p53蛋白的小分子化合物作用机制进行梳理,以期为后续开发靶向突变p53蛋白药物的创新提供帮助。展开更多
基金supported by the National Key Program of Research and Development,Ministry of Science and Technology of China (2022YFF1301600)National Natural Science Foundation of China (32070409,32270453 to S.X.X.)+1 种基金Priority Academic Program Development of Jiangsu Higher Education Institutions to G.Y.and S.X.X.Qing Lan Project of Jiangsu Province to S.X.X.
文摘DEAR EDITOR,Despite the generally increased cancer risk in large,long-lived organisms,cetaceans,among the largest and longest-living mammals,appear to possess a counteracting mechanism.Nevertheless,the genetic basis underlying this mechanism remains poorly understood.The p53 pathway serves as an ideal target for studying the mechanisms behind cancer resistance,as most cancer types have evolved strategies to circumvent its suppressive functions.
文摘BACKGROUND: It is of significance for single nucleotide polymorphisms (SNPs), a difference of rank, which exists widely in biology, genetics and other fields. OBJECTIVE: To detect polymorphism sites in exon-4 of p53 gene, promotor of Fas gene and intron-7 of Fas gene of healthy people in Han nationality in Zhejiang province. DESIGN: Simple random sampling. SETTING: Department of Surgery of the 118 Hospital of Chinese PLA.PARTICIPANTS: A total of 80 healthy people in Han nationality were selected from hospitals in Zhejiang province from August 2005 to January 2006. There were 43 males and 37 females aged from 3 to 78 years with the mean age of 39.5 years, and all subjects were consent. DNA which was used in genetic analysis was selected from peripheral venous blood of all subjects and maintained at -20℃.METHODS: Polymorphism sites in exon-4 of p53 gene, promotor of Fas gene and intron-7 of Fas gene were detected with directly DNA sequencing technique. MAIN OUTCOME MEASURES : Polymorphism sites in exon-4 of p53 gene, promotor of Fas gene and intron-7 of Fas gene of healthy people in Han nationality in Zhejiang province. RESULTS: A total of 80 samples were involved in the final analysis. SNPs sites were found at the 119^th base of exon-4 of p53 gene (the 72^nd codon of p53 gene), the 670^th base of upper start codon in promotor of Fas gene (Fas-670), and the 995^th base of intron-7 of Fas gene, especially SNPs in the 995^th base of intron-7 pf Fas gene, i.e. C→A transversion, was a new site.CONCLUSION : One unknown SNPs site is discovered in intron-7 of Fas gene of people in Han nationality in Zhejiang province. This study also proves that the 72^nd codon exists in p53 gene and the -670 polymorphism site exists in promotor of Fas gene.
基金the scientific research fundation of Shandong Provincial Education Committee(J94,K26)
文摘AIM: To investigate the possible roles of p53 and C-mycgenes in the primary hepatocellular carcinogenesis and therelationship between the liver hyperplastic nodule(LHN) andhepatocellular carcinoma(HCC).METHODS: The expression of p53 and C-myc genes wasdetected immunohist-ochemically in 73 and 60 cases of HCCand pericarcinomatous tissues, respectively .RESULTS: The positive expression of p53 in HCC wassignificantly higher than that in pericarcinomatous tissues(P<0.05). In pericarcinomatous tissues, the p53 expressionwas observed only in LHN, but not in liver cirrhosis (LC) andnormal liver tissues. The positive expression rate of C-mycin HCC or LHN was significantly higher than that in LC ornormal liver tissues (P<0.05 and P<0.01), however, nosignificant difference was found between HCC and LHN(P>0.05). The positive expression rate of p53 and C-myc inHCC was correlated with the histological differentiation, thatin the poorly differentiated was significantly higher than thatin well differentiated samples (P<0.05).CONCLUSION: The overexpression of p53 and C-myc genesmight play a role in the carcinogenesis of HCC; And LHNseems a preneoplastic lesion related to hepatocarcinogenesis;No evidence supports that LC contribute directly to thehepatocarcinogenesis.
文摘AIM: This study investigated the anti-cancer effect ofcombined quercetin and a recombinant adenovirus vectorexpressing the human p53, GM-CSF and B7-1 genes(designated BB-102) on human hepatocellular carcinoma(HCC) cell lines in vitro.METHODS: The sensitivity of HCC cells to anticancer agentswas evaluated by 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The viability of cells infectedwith BB-102 was determined by trypan blue exclusion. Theexpression levels of human wild-type p53, GM-CSF and B7-1genes were determined by Western blot, enzyme-linkedimmunosorbent assay (ELISA) and flow cytometric analysis,respectively. The apoptosis of BB-102-infected or quercetin-treated HCC cells was detected by terminal deoxynucleotidyltransferase (TdT) assay or DNA ladder electrophoresis.RESULTS: Quercetin was found to suppress proliferation ofhuman HCC cell lines BEL-7402, HUH-7 and HLE, with peaksuppression at 50 μmol/L quercetin. BB-102 infection wasalso found to significantly suppress proliferation of HCC celllines. The apoptosis of BB-102-infected HCC cells was greaterin HLE and HUH-7 cells than in BEL-7402 cells. Quercetin didnot affect the expression of the three exogenous genes inBB-102-infected HCC cells (P>0.05), but it was found to furtherdecrease proliferation and promote apoptosis of BB-102-infected HCC cells.CONCLUSION: BB-102 and quercetin synergeticallysuppress HCC cell proliferation and induce HCC cell apoptosis,suggesting a possible use as a combined anti-cancer agent.
基金National Science Fund for Distinguished Young Scholars,No.30125017the Major State Basic Research Development Program of China(973 Program),No.G1998051203
文摘AIM: To verify the effectiveness of denaturing highperformance liquid chromatography (DHPLC) in detecting somatic mutation of p53 gene in gastric carcinoma tissues.The superiority of this method has been proved in the detection of germline mutations, but it was not very affirmative with respect to somatic mutations in tumor specimens. ST7 gene, a candidate tumor suppressor gene identified recently at human chromosome 7q31.1, was also detected because LOH at this site has also been widely reported in stomach cancer.METHODS: DNA was extracted from 39 cases of surgical gastric carcinoma specimen and their correspondent normal mucosa. Seven fragments spanning the 11 exons were used to detect the mutation of p53 gene and the four exons reported to have mutations in ST7 gene were amplified by PCR and directly analyzed by DHPLC without mixing with wild-type allele.RESULTS: In the analysis of p53 gene mutation, 9 aberrant DHPLC chromatographies were found in tumor tissues, while their normal-adjacent counterparts running in parallel showed a normal shape. Subsequent sequencing revealed nine sequence variations, 1 polymorphism and 8 mutations including 3 mutations not reported before. The mutation rate of p53 gene (21%) was consistent with that previously reported. Furthermore, no additional aberrant chromatography was found when wild-type DNA was added into the DNA of other 30 tumor samples that showed normal shapes previously. The positivity of p53 mutations was significantly higher in intestinal-type carcinomas (40 %) than that in diffuse-type (8.33 %) carcinomas of the stomach. No mutation of ST7 gene was found.CONCLUSION: DHPLC is a very convenient method for the detection of somatic mutations in gastric carcinoma. The amount of wild type alleles supplied by the non-tumorous cells in gastric tumor specimens is enough to form heteroduplex with mutant alleles for DHPLC detection. ST7 gene may not be the target gene of inactivation at 7q31 site in gastric carcinoma.
文摘AIM: To determine bhe accuracy of p53 gene mutations predicted by overexpression of p53 protein immunohistochemically,and to investigate the co-mutation of p53 and K-ras genes in rectal cancer and its effect on promoting malignant biologic behaviors of tumors.METHODS: Ninety-seven specimens of rectal cancer were surgically resected in our hospital from August 1996 to October 1997. The hot mutation areas of p53 gene (in exons 5-8) and K-rasgene (in codon 5/12 and 13) were detected with polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), and overexpression of p53 protein was detected with immunohistochemistry (IHC) in the 97 specimens of rectal cancer. Correlation between gene mutations and tumor clinicopathologic factors was studied, and survival analysis was penfomed as well.RESULTS: There were 36 cases of p53 gene mutations in 61 p53 protein positive cases, and 21 cases of p53 gene non-mutation in 36 p53 protein negative cases respectively.The coincidence rate of p53 gene mutation by IHC method with PCR-SSCP method was 58.8% (57/97). The mutation rate of p53 gene was 52.6% (51/97), while K-ras gene mutation was observed in codons 12 and 13 in 61 cases with a mutation rate of 62.9% (61/97). Single gene mutation of p53 or K-raswas found in 32 cases. Both p53 and K-ras gene mutation were found in 48 cases. Statistical analysis showed that p53 and K-ras gene mutations were not related to the dinicopathologic factors, including tumor size, gross tumor type, histological dassification, differentiation, invasion to intestinal veins, lymphatics and nerves, invasive depth to.wall, lymph node metastasis, and Dukes' stages (P>0.05).The survival in patients with no gene mutation, single gene mutation and both gene mutations were similar (P>0.05).CONCLUSION: IHC has a certain false positive and false negative rate in detecting p53 gene mutations. Malignant biological behaviours of rectal cancer are not enhanced by p53 and K-rasgene mutations. Co-mutation of p53 and K-ras gene has neither synergic carcinogenesis-promoting effect,nor prognostic effect on rectal cancer.
基金supported by National Natural Science Foundation of China (NSFC) (Grant No. 30771194 and 31170735)
文摘Objective: Polycystic kidney disease(PKD) is the major cause of kidney failure and mortality in humans. It has always been suspected that the development of cystic kidney disease shares features with tumorigenesis, although the evidence is unclear.Methods: We crossed p53 mutant mice(p53N236S, p53S) with Werner syndrome mice and analyzed the pathological phenotypes.The RNA-seq, ss GSEA analysis, and real-time PCR were performed to dissect the gene signatures involved in the development of disease phenotypes.Results: We found enlarged kidneys with fluid-filled cysts in offspring mice with a genotype of G3mTerc^(-/-)WRN^(-/-)p53^(S/S)(G3TM).Pathology analysis confirmed the occurrence of PKD, and it was highly correlated with the incidence of tumorigenesis. RNA-seq data revealed the gene signatures involved in PKD development, and demonstrated that PKD and tumorigenesis shared common pathways, including complement pathways, lipid metabolism, mitochondria energy homeostasis and others. Interestingly, this G3TM PKD and the classical PKD1/2 deficient PKD shared common pathways, possibly because the mutant p53S could regulate the expression levels of PKD1/2, Pkhd1, and Hnf1b.Conclusions: We established a dual mouse model for PKD and tumorigenesis derived from abnormal cellular proliferation and telomere dysfunction. The innovative point of our study is to report PKD occurring in conjunction with tumorigenesis. The gene signatures revealed might shed new light on the pathogenesis of PKD, and provide new molecular biomarkers for clinical diagnosis and prognosis.
基金National Natural Science foundation of China, No.39470332
文摘Objective:To study the role of the mutations of p53, APC and K-ras genes in 47 cases of 3 types of intestinal metaplasia (IM) of gastric mucosa. Methods:In 47 cases of IM, exons 5- 8 of p53 and exons 15 of APC were examined with PCR-SSCP and codon 12 of K-ras with PCR-RFLP to detect the existence of any mutations of these structures. Results:Muta- tions of p53, APC and K-ras were found in 29.8% (14/47),6.4% (3/47) and 6.4% (3/47) respectively in our series of patients who consisted of 33 with types I and II and 14 with type III of IM. The mutation rate of p53 was far higher in patients with type III IM (57.1%,8/14) than in those with types I and II IM(18.2%,6/33)(P <0.05). Though the mutation rate of APC and K-ras was also higher in the patients with type III IM than in those with types I and II IM, it was of no statistical significance (P >0.05). In one case of type III IM, mutation of both p53 and K-ras was found. Conclusion: The molecular changes of 3 types of IM are different. The mutation of p53 may be closely related to carcinogenesis in cases of type III IM and it serve as a sign for the early diagnosis of gastric carcinoma.
文摘p53蛋白是人体内十分重要的肿瘤抑制因子,通过调节细胞周期阻滞、诱导细胞凋亡等作用发挥肿瘤抑制功能。突变后的p53蛋白不仅具有显性负性效应(dominant negative effect,DN)抑制野生型p53蛋白功能,而且还通过功能获得性效应(gain of function,GOF)调节细胞代谢、侵袭、迁移等方式促进肿瘤的发生。p53蛋白在超过50%的肿瘤组织中发生突变,是肿瘤细胞区别于正常细胞的一个特异性药物靶点。因此,针对突变p53蛋白开发新型抗癌药物一直是研究的热点。长期以来,由于突变p53蛋白表面较为光滑,缺乏药物结合口袋,使其被认为是一个不可成药的靶点。随着高通量筛选技术的发展以及对突变p53蛋白结构的深入了解,许多靶向突变p53蛋白的小分子化合物被报道并在体外展现出较好的抗肿瘤活性,多款基于突变p53蛋白研发的化合物已经进入临床试验阶段。本文就靶向p53蛋白治疗肿瘤的直接和间接策略进行综述,重点针对突变p53蛋白重激活剂与降解突变p53蛋白的小分子化合物作用机制进行梳理,以期为后续开发靶向突变p53蛋白药物的创新提供帮助。