pten and tumor

1、<p>　　PTEN and Tumor</p><p>　　Abstract. PTEN was the firstly found cancer suppressor gene with dual-specificity phosphatase (DPS) activities. The gene has connection with the sporadic tumors and heredit

2、ary diseases characterized by tumor-like growth in humans. PTEN can specifically dephosphorylate the phosphatidylinositol-3, 4, 5-triphosphoric acid [PIP3], and antagonize PI3K-AKT signaling pathway to be at work, and he

3、nce regulates the growth, multiplication, migration and apoptosis of cells. PTEN mutations are mainly reflec</p><p>　　Key words: cancer suppressor gene, PTEN, tumor, phosphatase </p><p>　　1. Int

4、roduction </p><p>　　The occurrance, development, invasion and metastasis of tumor are processes of changes in multiple factors, steps and genes, in which the activation of cancer genes and the inactivation o

5、f cancer suppressor genes are important factors. Li et al [1] (1997) cloned a new gene when researching the primary breast cancer 10q23 homology loss region and named it "phosphatase and tensin homology deleted on c

6、hromosome 10" (PTEN). In the same year, Steck et al [2] cloned a tumor suppressor gene in 10q23。3 </p><p>　　2. Molecular Structure and Biological </p><p>　　Characteristics of PTEN </p>

7、;<p>　　PTEN, a total length of 200kb, is situated in the chromosome 10q23.3, and has 9 exons and 8 intrones; and the length of its mRNA is 5.5kb. PTEN, whose main structure functional region is in N-terminal, and

8、cDNA sequence has an open reading frame composed of 1209 nucleotides and encodes 403 amino acids to constitute a polypeptide chain, and amino acid sequence is highly homogenous with protein tyrosine phosphatase and serin

9、e threonine phosphatase catalytic domain structural motif, was the firstly</p><p>　　3.1 Suppressing Cell Growth and Enhancing Apoptosis </p><p>　　Under the extracellular signalization of some gr

10、owth factors such as IGF, EGF and PDGF, the intracellular phosphatidylinositol 3-kinases (PI3K) can be activated, hence making the second messenger PIP3 in cell membrane activated; then, the activated PIP3 can activate p

11、rotein kinase B (PKB) and AKT in cell membrane, hencing making cells into division cycle and suppressing apoptosis. Besides, AKT can dephosphorylate the original antiapoptotic factor Bad and Caspase-9 to be inactivated,

12、hence preven</p><p>　　3.2 Suppressing the Adhesion and Migration of Tumor Cell </p><p>　　Focal adhesion kinase (FAK) is the important molecule of the integrin mediated signal transduction pathwa

13、ys. Integrin combines FAK by forming skeleton complex and make FAK tyrosine dephosphorylated until inactivated, resulting in the improvement of FAK tyrosine dephosphorylation level and increasing the activity of phosphok

14、inase, and hence activates the signal transduction molecules of several kinases related to it, enhancing the invasion migration of cells. PIEN can decrease FAK tyrosine dephos</p><p>　　The growth, invasion a

15、nd migration of tumor have close connection with the vascular formation, while the vascular formation process is regulated by angiogenesis factor and vascular suppressing factor. The mutation or loss of PTEN can promote

16、the formation of vascular endothelial growth factor and then make the vascular endothelial cell multiplication and tumor capillaries formed, hence increasing the invasion and migration intensity of tumor cells. The mutat

17、ion or loss of PTEN may, through the P</p><p>　　4. Mutation and Expression Deletion of PTEN in Tumor </p><p>　　The expression levels of all kinds of normal tissues in humans, such as placenta, k

18、idney, liver and brain, are high. The abnormal expression of somatic cell PTEN is often seen in multiple sporadic tumors such as glioblastoma multiforme, prostatic cancer, endometrial cancer, thyroid cancer, melanoma, lu

19、ng cancer, gastrointestinal tumor, and mouth and hematologic tumors. The forms of PTEN expression abnormality mainly include gene mutation and deletion. </p><p>　　4.1 Gene Mutation </p><p>　　PTE

20、N mutation means that it losses the negative regulation function on cell growth and results in the occurrance of tumor. Based on the mutation sources, PTEN mutation can be divided into germ line mutation and somatic muta

21、tion; and the mutation types include missense mutation, nonsense mutation, insertion and deletion, frameshift mutation and splicing mutation. The nine exons and some intrones in PTEN can be mutated, but the mutation is m

22、ainly distributed in exon 5 and exon 8 which are just in </p><p>　　Endometrial cancer PTEN mutation is characterized by high rates of nonsense mutation and frameshift mutation; the diagnostic rate of endomet

23、rial cancer PTEN mutation is 33%-35%. The mutation often occurs in the well-differentiate advanced invasive cancer patients, showing that PTEN mutation has connection with the starting and ending of endometrial cancer ch

24、anges. Yao et al[14] diagnosed the PTEN/MMACI mutations of 96 primary liver cancer cases, and analyzed the gene complete sequence and showed</p><p>　　PTEN express abnormality is mainly caused by genic mutati

25、on and deletion. In many primary tumors, LOH is hihly common, and its occurring rate in prostatic cancer, endometrial cancer and advanced glioblastoma multiforme is 60%-80% [15]. However, in early tumors, the complete de

26、letion of PTEN occurs only in endometrial cancer and ovarian cancer. Most PTEN complete inactivations occur in advanced tumors such as prostatic cancer and kidney cancer. </p><p>　　Fujiward et al [16] found

27、the 10q of 12 cases had a locus at least to have allele deletion in 37 cases of HCC, and 8 cases had part of deletion. Tashiro et al [17] used the microsatellites around 5 PTENs to mark D10s541, D10s215, D10s608, D10s610

28、 and D10s169 to analyze the LOH of endometrial cancer in this region, finding 56% of them at least to carry one of deletions in this region and the deletion occurring to 44% of them near the 5 markers, and simultaneously

29、 there were PTEN mutations to acco</p><p>　　Some researches [20] also discovered that microsatellite instability (MSI) led to PTEN expression deletion. In the researches, the MSI (+) endometrial cancer фPTEN

30、 mutation rate was found to be 78%; MSI (-) mutation rate was only 35% (P<0.05); the occurrance of MSI had connection with DNA mismatch repair (MMR) gene expression inactivation, and also resulted in the complexity of

31、 PTEN expression regulation function. 　　PTEN was the firstly found cancer suppressor gene with dual-specificity phospha</p><p>　　References </p><p>　　[1] Li J, Yen C, liaw D, et al. PTEN, a put

32、ative protein tyrosine phosphatase gene mutated in human brain, breast and prostate cancer [J]. Science, 1997, 275(5308):1943-1947. </p><p>　　[2] Steck PA, Pershouse MA, Jasser SA, et al. Identification of a

33、 candidate tumor suppnessor gene, MMAcl, at chromosome 10923.3 that is mutaese in multiple advanced cancers [J]. Nat Genet, 1977, 15(4):356~362. </p><p>　　[3] Li DM, Sun H. TEPL, encoded by a candidate tumor

34、 suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta [J]. Cancer Res, 1997, 57(11):2124-2129. </p><p>　　[4] Dahia FL. PTEN, a unique tumor suppressor gene [

35、J]. Endocr Relat cancer, 2000, 7(2):115-129. </p><p>　　[5] Knistin A Waite, charis Eng. Protean PTEN: Form and Function [J]. Am J Hum. Genet, 2002, 70(9):829-844. </p><p>　　[6] Weng C P, Gimm V,

36、 Kum JB, et al. Transient ectopic expression of PTEN in thyroid cancer cell lines induces cell cycle arrest and cell type-dependent cell death [J]. Hum Mol Genet, 2001, 10(3):251-258. </p><p>　　[7] Yuan XJ,

37、Whang YE. PTEN Sensitizers prostate cancer cells to death receptor mediated and drug induced apoptosis through a FADD-dependent pathway [J]. Oncogene, 2002, 21(2):319-327. </p><p>　　[8] Brunet A, Bonni A, Zi

38、gmond MJ, et al ART promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor [J]. Cell 1999, 86(6):857-868. 　　[9] Tumuru M, Gu J, Takino, et al. Tumor suppressor PTEN inhibition of cell i

39、nvasion migration, and growth differential involvement of focal adhesion kinase and p130cas [J]. Cancer Res, 1999, 59(2):442-449. </p><p>　　[10] Tamuram, Gu J, Matsumoto K, et al. lnhibition of cell migratio

40、n, spreading, and focal adhesions by tumor suppressor PTEN [J]. Science, 1998, 280(5369):1614-1617. </p><p>　　[11] Rustia A, Wierzbicki V, Marrocco L, et al. Is exon 5 of the PTEN MMACL gene a prognostic mar

41、ker in and plastic glioma [J]. Neurosurg Rev, 2001, 24(2-3):47-102. </p><p>　　[12] Eng C. PTEN: one gene, many syndromes [J]. Hum Mutat, 2003, 22(3):183-198. </p><p>　　[13] Marsh DJ. Dahia PLM,

42、zheng I, et al. PTEN mutation spectrum and genotype-yan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome [J]. Hum Mol Genet, 1999, 8(8):1461-1472. </p><p>　　[14] Yao YJ, Ping XL, zhang H

43、, et al. PTEN/MMACL mutations in hepatocellular carcinomas [J]. Oncogene, 1999, 18(20):3181-3185. </p><p>　　[15] Dahia PL. PTEN, a unique tumor suppressor gene [J]. Endocr Relat Cancer, 2000, 7(2):115-129. &

44、lt;/p><p>　　[16] Fujiwara Y, Hoon Ds Yamada T, et al. PTEN/MMACL mutation and frequent loss of heterozygosity identified in chromisome 10q in a subset of hepatocellular carcinoma [J]. Jpn J cancer Res, 2000, 91

45、(3):287-292. </p><p>　　[17] Tashiro H, Blazes MS, Wu R, et al. Mutations in PTEN core frequent in endometrial carcinoma but rare in other Common gynecological malignancies [J]. Cancer Res, 1997, 57(18):3935-

46、3940. </p><p>　　[18] Lu Qing-jie, ZHAO Xiao-dong, SONG Ji-ye, et al. Research on the mechanisms of PTEN gene inactivation in ovarian Cancer [J]. Chin J pathol, 2005, 34(5):266-269. </p><p>　　[19

47、] Young-Hwa k, Hye SL, Woo HK. Promoter Methylation and Silencing of PTEN in Gastric Carcinoma [J]. Lab lnvest, 2002, 82(3):258-291. </p><p>　　[20] Kong D, Suzuki A, Zou, TT, et al. PTEN is frequently mutate

48、d in primary endometrial carcinomas [J]. Nat Genet, 1997, 17(2):143-144. </p><p>　　[21] Goel A, Arnold CN, Niedz wiecki D, et al. Freguent inactivation of PTEN by promoter hypermethylation in microsatellite