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PubMed2004

PTEN up-regulates the tumor metastasis suppressor gene Drg-1 in prostate and breast cancer.

PTEN (phosphatase and tensin homologue deleted on chromosome 10) has been shown to be inactivated in a wide variety of cancers, and the role of this gene as a tumor suppressor has been well established. On the other hand, results of recent animal studies as well as clinical evidence indicate that PTEN is also involved in tumor metastasis suppression. Although PTEN is known to play a key role in controlling cell growth and apoptosis, how PTEN exerts the metastasis suppressor function remains largely unknown. Recently, a microarray analysis identified the Drg-1 gene (differentiation related gene 1) as one of the potential targets of PTEN. The Drg-1 gene has been shown to suppress tumor metastasis in animal models of prostate and colon cancer, and the expression of this gene is significantly reduced with advancement of prostate and breast cancers in clinical setting. In this study, we explored the possibility that PTEN controls tumor metastasis by regulating the expression of the Drg-1 gene. Our results indicate that overexpression of PTEN significantly augments the endogenous expression of Drg-1 protein, whereas inhibition of PTEN by small interfering RNA decreases Drg-1 in a dose- and time-dependent manner. We also found that the control of the Drg-1 gene by PTEN seems to be at the transcriptional level, and that a phospho-Akt inhibitor restores the Drg-1 expression, indicating that PTEN controls Drg-1 by an Akt-dependent pathway. Consistent with these results, our immunohistochemical analysis revealed that PTEN expression correlates significantly with Drg-1 in both prostate and breast cancer cases. Furthermore, combination of the two markers, PTEN and Drg-1, emerged as a significantly better predictor of prostate and breast cancer patient survival than either marker alone.

Breast Neoplasms↗
PubMed2006

Nuclear localization of PTEN is regulated by Ca(2+) through a tyrosil phosphorylation-independent conformational modification in major vault protein.

We have recently shown in MCF-7 cells that nuclear phosphatase and tensin homologue deleted on chromosome 10 (PTEN) down-regulates phosphorylation of p44/42 and cyclin D1 and induces G(1) cell cycle arrest, whereas cytoplasmic PTEN down-regulates phosphorylation of Akt, up-regulates p27, and induces apoptosis. In this manner, nucleocytoplasmic partitioning of PTEN seems to differentially regulate the cell cycle and apoptosis. We have also reported that PTEN has nuclear localization signal-like sequences required for major vault protein (MVP)-mediated nuclear translocation. To date, several other proteins are reported to interact with MVP, including extracellular signal-regulated kinases and steroid receptors, suggesting that MVP is likely to be involved in signal transduction through nucleocytoplasmic transport. However, the exact mechanism of MVP-mediated nucleocytoplasmic shuttling remains elusive. PTEN reportedly interacts in vitro with the EF hand-like motif of MVP in a Ca(2+)-dependent manner. The current study shows that small interfering RNA-mediated MVP silencing decreases the nuclear localization of PTEN and increases phosphorylation of nuclear p44/42. We show in situ that PTEN-MVP interaction is Ca(2+) dependent and is abolished by Mg(2+). Nuclear localization of PTEN is decreased by increasing Ca(2+) levels in culture medium in a dose-dependent manner. Ca(2+) ionophore A23187 increases nuclear localization of PTEN and decreases phosphorylation of nuclear p44/42. Finally, we show that Ca(2+)-dependent PTEN-MVP interaction is not related to MVP's tyrosil phosphorylation but rather due to its conformational modification. Our observations suggest that Ca(2+) regulates PTEN's nuclear entry through a tyrosil phosphorylation-independent conformational change in MVP. Collectively, our data present evidence of a novel crosstalk between the Ca(2+) signaling-mediated regulation of the cell cycle and MVP-mediated nuclear PTEN localization and function.

Apoptosis↗
PubMed2005

Negative regulation of CXCR4-mediated chemotaxis by the lipid phosphatase activity of tumor suppressor PTEN.

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a multifunctional tumor suppressor, has been shown to play a regulatory role in cell migration. Dictyostelium discoideum cells lacking PTEN exhibited impaired migration toward chemoattractant gradients. In the present study, we investigated the involvement of PTEN in chemotaxis of mammalian cells by examining PTEN-null Jurkat T cells. We observed that, in contrast to observations made in D discoideum, PTEN-null Jurkat T cells exhibited potent chemotactic responses to the chemokine stromal cell-derived factor 1alpha (SDF-1alpha), indicating that PTEN was not requisite for CXC chemokine receptor 4 (CXCR4)-mediated chemotaxis of Jurkat cells. Conversely, reconstitution of PTEN in Jurkat cells by using a tetracycline (Tet-on)-inducible expression system down-regulated CXCR4-mediated chemotaxis. Furthermore, we established the lipid phosphatase activity of PTEN as essential for its inhibitory effect on chemotaxis. In addition, using PTEN-expressing T-cell lines and primary T cells, we demonstrated that down-regulation of PTEN expression with vector-based small interfering RNAs (siRNAs) enhanced CXCR4-mediated chemotaxis. Based on these results, we conclude that PTEN expression negatively regulates chemotaxis of lymphoid mammalian cells via its lipid phosphatase activity. Our findings may account for the reported increase in metastatic activity of PTEN-null tumor cells.

Animals↗
PubMed2001

PTEN deficiency: a role in mammary carcinogenesis.

The PTEN gene is often mutated in primary human tumors and cell lines, but the low rate of somatic PTEN mutation in human breast cancer has led to debate over the role of this tumor suppressor in this disease. The involvement of PTEN in human mammary oncogenesis has been implicated from studies showing that germline PTEN mutation in Cowden disease predisposes to breast cancer, the frequent loss of heterozygosity at the PTEN locus, and reduced PTEN protein levels in sporadic breast cancers. To assay the potential contribution of PTEN loss in breast tumor promotion, Li et al. [1] crossed Pten heterozygous mice with mouse mammary tumor virus-Wnt-1 transgenic (Wnt-1 TG, Pten+/-) mice. Mammary ductal carcinoma developed earlier in Wnt-1 TG, Pten+/- mice than in mice bearing either genetic change alone, and showed frequent loss of the remaining wild-type PTEN allele. These data indicate a role for PTEN in breast tumorigenesis in an in vivo model.

Animals↗
PubMed2003

Loss of PTEN expression followed by Akt phosphorylation is a poor prognostic factor for patients with endometrial cancer.

To clarify whether and how PTEN and the phosphatidylinositol 3-kinase/Akt pathway relates to endometrial cancer we examined the expression of these pathway-related proteins in patients with endometrial cancer. Of 103 endometrial cancers, 37 (36%) showed negative immunohistochemical staining for PTEN. Western blotting revealed that the level of phosphorylated Akt expression in PTEN-negative cases was significantly higher compared with that in positive cases. We found a significant inverse correlation between PTEN and phosphorylated Akt. The present study indicates the phosphorylation of Akt accompanied by the loss of PTEN in clinical specimens of endometrial cancers. In order to investigate the relationship between PTEN expression and prognosis in endometrial cancer, 98 patients with advanced endometrial cancer were newly enrolled. The survival rate for PTEN-positive patients was significantly higher than that for PTEN-negative or -heterogeneous staining patients. Of the 98 patients, 25 underwent radiation therapy, 62 received chemotherapy after surgery, and the remaining 11 did not have any postoperative treatment. When patients underwent chemotherapy, the survival rate for PTEN-positive cases was clearly higher than that for PTEN-negative or -heterogeneous cases (62.4 vs 11.8%). Subsequent multivariate analysis revealed that PTEN staining was an independent prognostic factor for patients undergoing chemotherapy. The current study demonstrates that PTEN-positive staining is a significant prognostic indicator of favorable survival for patients with advanced endometrial cancer who undergo postoperative chemotherapy.

Adult↗
PubMed2003

PTEN encoding product: a marker for tumorigenesis and progression of gastric carcinoma.

AIM: To detect the expression of PTEN encoding product in normal mucosa, intestinal metaplasia (IM), dysplasia and carcinoma of the stomach, and to investigate its clinical implication in tumorigenesis and progression of gastric carcinoma. METHODS: Formalin-fixed paraffin embedded specimens from 184 cases of gastric carcinoma, their adjacent normal mucosa, IM and dysplasia were evaluated for PTEN protein expression by SABC immunohistochemistry. PTEN expression was compared with tumor stage, lymph node metastasis, Lauren's and WHO's histological classification of gastric carcinoma. Expression of VEGF was also detected in 60 cases of gastric carcinoma and its correlation with PTEN was concerned. RESULTS: The positive rates of PTEN protein were 100 %(102/102), 98.5 %(65/66), 66.7 % (4/6) and 47.8 %(88/184) in normal mucosa, IM, dysplasia and carcinoma of the stomach, respectively. The positive rates in dysplasia and carcinoma were lower than in normal mucosa and IM (P<0.01). Advanced gastric cancers expressed less frequent PTEN than early gastric cancer (42.9 % vs 67.6 %, P<0.01). The positive rate of PTEN protein was lower in gastric cancer with than without lymph node metastasis (40.3 % vs 63.3 %, P<0.01). PTEN was less expressed in diffuse-type than in intestinal-type gastric cancer (41.5 % vs 57.8 %, P<0.05). Signet ring cell carcinoma showed the expression of PTEN at the lowest level (25.0 %, 7/28); less than well and moderately differentiated ones (P<0.01). Expression of PTEN was not correlated with expression of VEGF (P>0.05). CONCLUSION: Loss or reduced expression of PTEN protein occures commonly in tumorigenesis and progression of gastric carcinoma. It is suggested that PTEN can be an objective marker for pathologically biological behaviors of gastric carcinoma.

Biomarkers, Tumor↗
PubMed2001

PTEN mutation located only outside exons 5, 6, and 7 is an independent predictor of favorable survival in endometrial carcinomas.

Although the prognostic impact of PTEN mutation in endometrial carcinoma is beginning to be analyzed, the prognostic significance of mutated PTEN exons has not ever been described. Sixty-seven endometrial carcinomas were analyzed for PTEN mutations using single-strand conformation polymorphism analysis and DNA sequencing. First, survival rates were compared according to PTEN status and mutated PTEN exons. Subsequently, univariate and multivariate analyses of various favorable prognostic factors for survival were conducted. The associations between PTEN mutation and clinicopathological features were also statistically evaluated. PTEN mutations were detected in 37 of 67 (55%) specimens. Among 47 mutations, frameshifts (57%) and mutations in exon 8 (38%) were most frequent. In univariate analysis, a factor of PTEN mutation only outside exons 5-7 was associated with significantly better survival (P = 0.02), although mutation in any exon of PTEN was not (P = 0.33). Subsequent multivariate analysis revealed that factors of mutation only outside exons 5-7 of PTEN, stage I/II, and G1 were significant and independent prognostic indicators for favorable survival (P = 0.004, 0.004, and 0.0006, respectively). In the subset of advanced-stage disease, mutation only outside exons 5-7 was associated with a trend toward better survival (P = 0.13). No significant correlation was observed between PTEN mutation and estrogen-related clinicopathological features. In conclusion, we find that PTEN mutation located only outside exons 5-7 is a significant and independent positive prognostic indicator for survival. The current observation has prognostic and therapeutic implications for the management of patients with endometrial carcinoma.

Adult↗
PubMed2002

Inactivation of the PTEN gene by mutation, exonic deletion, and loss of transcript in human oral squamous cell carcinomas.

PTEN, a tumor suppressor gene, has been found to be inactivated by structural abnormalities or epigenetic changes in several types of human cancers. Recently, several studies have also suggested the possibility that the PTEN gene is a target of genomic instability in human cancers displaying microsatellite instability (MSI). To investigate the role of PTEN in human oral squamous cell carcinomas, we screened the entire coding region sequences and examined the expression of the PTEN gene in 81 oral cancers displaying microsatellite stability (MSS) and 5 oral cancers displaying MSI. Mutation of the PTEN gene was identified in one MSS cancer (1/81; 1.2%) and three MSI cancers (3/5; 60%). The MSS cancer harbored a missense mutation from Ala (GCA) to Val (GTA) at codon 137. Of the MSI cancers containing the PTEN mutation, case 36 had a missense mutation from Lys (AAA) to Glu (GAA) at codon 254, case 43 contained a frameshift mutation (one A deletion) in a 6 bp poly(A) tract affecting codon 265-267, and case 64 harbored two missense mutations from Val (GTG) to Ala (GCG) at codon 222, and from Gly (GGA) to Arg (AGA) at codon 230 indicating biallelic mutation of PTEN. Genomic deletion of exon 5, resulting in loss of PTEN mRNA, was observed in two MSS cancers. In spite of an intact PTEN gene, one MSS and one MSI cancer lacked PTEN mRNA. These findings suggest that the inactivation of PTEN by either mutation or loss of transcript plays a role in the pathogenesis of some oral cancers (8/86; 9.3%). Furthermore, inactivation of PTEN was far more frequent in MSI oral cancers (4/5; 80%) than in MSS oral cancers (4/81; 4.9%).

Adult↗
PubMed2002

Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells.

Phosphatase and tensin homologue deleted from chromosome 10 (PTEN) is a lipid phosphatase with putative tumor suppressing abilities, which is frequently mutated in prostate cancer. Loss of PTEN leads to constitutive activation of the phosphatidylinositol 3'-kinase/serine-threonine kinase (Akt) signal transduction pathway and has been associated with resistance to chemotherapy. This study aimed to determine the effects of PTEN status and treatment with rapamycin, an inhibitor of mTOR, in the response of prostate cancer cell lines to doxorubicin. The DU-145 PTEN-positive cell line was significantly more susceptible to the antiproliferative effects of doxorubicin as compared with the PTEN-negative PC-3 cell line. Transfection of PTEN into the PC3 cells decreased the activation of Akt and the downstream mTOR-regulated 70-kDa S6 (p70(s6k)) kinase and reversed the resistance to doxorubicin in these cells, indicating that changes in PTEN status/Akt activation modulate the cellular response to doxorubicin. Treatment of PC-3 PTEN-negative cells with rapamycin inhibited 70-kDa S6 kinase and increased the proliferative response of these cells to doxorubicin, so that it was comparable with the responses of PTEN-positive DU-145 cells and the PC-3-transfected cells. Furthermore, treatment of mice bearing the PTEN-negative PC-3 prostate cancer xenografts with CCI-779, an ester of rapamycin in clinical development combined with doxorubicin, inhibited the growth of the doxorubicin-resistant PC-3 tumors confirming the observations in vitro. Thus, rapamycin and CCI-779, by interacting with downstream intermediates in the phosphatidylinositol 3'-kinase/Akt signaling pathway, reverse the resistance to doxorubicin conferred by PTEN mutation/Akt activation. These results provide the rationale to explore in clinical trials whether these agents increase the response to chemotherapy of patients with PTEN-negative/Akt active cancers.

Animals↗
PubMed2002

PTEN suppresses hyaluronic acid-induced matrix metalloproteinase-9 expression in U87MG glioblastoma cells through focal adhesion kinase dephosphorylation.

Glioblastoma is a severe type of primary brain tumor and its invasion is strongly correlated with the secretion of matrix metalloproteinases (MMPs). To investigate a role of PTEN, a tumor suppressor gene, in the regulation of hyaluronic acid (HA)-induced invasion of glioma cells, we examined the secretion of MMP-9 in various glioma cells with or without a functional PTEN gene. The secretion of MMP-9 in glioma cells lacking functional PTEN (U87MG, U251MG, and U373MG) was induced by HA, although not in wildtype (wt)-PTEN-harboring cells (LN229, LN18, and LN428). In addition, stable expression of wt-PTEN into U87MG cells significantly decreased the secretion of HA-induced MMP-9 and basal levels of MMP-2, inhibiting the activation of focal adhesion kinase and extracellular signal-regulated kinase 1/2, whereas the secretion levels of the tissue inhibitor of metalloproteinase-1 and -2 were increased, finally resulting in the inhibition of invasion by HA in vitro. Ectopic expressions of adenoviral (Ad)-wt-PTEN and -lipid phosphatase-deficient (G129E)-PTEN, but not both protein and -lipid phosphatase-deficient (C124S)-PTEN, reduced MMP-9 secretion and invasion by HA. These results were also confirmed by expressions of Ad-wt-PTEN and Ad-G129E-PTEN in other glioblastoma cells lacking functional PTEN, U251MG, and U373MG. These findings strongly suggest the possibility that PTEN may block HA-induced MMP-9 secretion and invasion through its protein phosphatase activity.

Focal Adhesion Kinase 1↗
PubMed2003

Loss of PTEN promotes tumor development in malignant melanoma.

Loss of tumor suppressor genes on chromosome 10 plays an important role in the development of 30-60% of melanomas; however, the identity of these genes and the mechanisms by which loss of these genes leads to tumor formation remain uncertain. The phosphatase and tensin homologue deleted from chromosome 10 (PTEN) is one of the genes on chromosome 10 whose of which the loss or inactivation may play an important role in melanoma tumorigenesis, but functional studies directly demonstrating PTEN involvement in melanomas are necessary to confirm this role. To determine the biological importance of PTEN loss in melanomas, we established a novel model in which an intact chromosome 10 was transferred into melanoma cells lacking PTEN protein to express the protein at normal physiological levels and to measure the consequent effects on melanoma tumorigenesis. PTEN expression in these cells retarded tumor development in mice unless, by analogy with loss of heterozygosity, the PTEN gene was deleted or inactivated during tumor formation. Mechanistically, PTEN loss led to the activation of Akt, which consequently down-regulated the apoptotic pathway of melanoma cells. In contrast, expression of PTEN attenuated Akt activation, thereby increasing sensitivity to apoptotic stimuli in cell culture and in vivo in animal models. This model demonstrated that PTEN loss is critical for melanoma tumorigenesis and allowed a dissection of the underlying mechanism by which PTEN loss facilitated melanoma tumor development. In summary, loss of PTEN reduces apoptosis and promotes cell survival, thereby favoring melanoma tumor formation. Thus, these observations provide an etiological basis for PTEN loss during the genesis of sporadic melanomas.

Apoptosis↗
PubMed2003

[PTEN expression and its significance in human primary hepatocellular carcinoma].

OBJECTIVES: To explore the significance of PTEN (phosphatase and tensin homolog deleted on chromosome 10) in the development of human primary hepatocellular carcinoma (HCC). METHODS: PTEN protein expression in cancerous liver tissues and paired para-carcinoma liver tissues from 60 HCC patients was detected by immunohistochemistry and PTEN mRNA expression was analyzed by northern blot. The significance of PTEN in the development of HCC was analyzed by investigating the relationship between the expression levels of PTEN protein and mRNA, and the clinicopathological parameters of HCC patients. RESULTS: PTEN protein was immunohistochemically stained in the cytoplasmic region of para-carcinoma liver tissues in all the 60 patients, while only 48.3% (29/60) of the patients were positive for PTEN protein in cancerous liver tissues. The positive rate of PTEN protein in HCC tissues were relative to the histological gading and the presence of tumor thrombus. In grade I - II, III, and IV, the positive rates were 84.0%, 23.8%, and 21.4% respectively, and in the group with tumor thrombus was 26.7%, while in the group without tumor thrombus was 55.6%. Northern blot showed that there existed four PTEN mRNA transcripts with the length of 5.5kb, 4.4kb, 2.4kb, and 1.8kb respectively. The level of PTEN mRNA expression in HCC tissues was much lower than that in the paired para-carcinoma liver tissues. The low expression level of the 5.5kb and 4.4kb transcripts was significantly associated with serum AFP value, presence of tumor thrombus, state of satellite lesion and histological grading. The low expression level of the 2.4kb transcript in HCC was significantly associated with the presence of tumor thrombus and satellite lesions in HCC patients. However, no evident relationship between the lowered expression level of the 1.8kb transcript and the clinicopathological parameters of HCC was observed in these 60 patients. CONCLUSIONS: Down-regulation of PTEN expression may play an important role in the development of HCC and the expression level of PTEN may be a potential adjuvant parameter in forecasting the progress and prognosis of HCC.

Adult↗
PubMed2004

Effects of mutation and expression of PTEN gene mRNA on tumorigenesis and progression of epithelial ovarian cancer.

OBJECTIVE: To investigate the mutation and expression of tumor suppressor gene-PTEN mRNA and explore their roles in tumorigenesis and progression of ovarian cancer. METHODS: Mutated exon 5 of PTEN gene was examined in normal ovary (n=5), ovarian cyst (n=5), ovarian borderline tumor (n=9), epithelial ovarian cancer (n=60), and ovarian cancer cell line (n=1) by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). mRNA expression of PTEN gene was evaluated in corresponding tissues and cell line by reverse transcription polymerase chain reaction (RT-PCR). The mutation and mRNA expression of PTEN gene were compared with clinicopathological features of ovarian cancer. RESULTS: Mutated exon 5 of PTEN gene was detected only in 5 (7.1%) cases of epithelial ovarian cancer. mRNA expression level of PTEN gene in ovarian borderline tumor or ovarian cancer was lower than that in normal ovary or ovarian cyst (P < 0.05). The level of PTEN gene mRNA expression was negatively correlated with clinicopathological staging of ovarian cancer, whereas positively correlated with histological differentiation (P < 0.05). mRNA expression level of PTEN gene in ovarian endometrioid cancer was significantly lower than that in ovarian serous or mucinous cancer (P < 0.05). CONCLUSIONS: Mutation of PTEN gene occurs in ovarian cancer. Down-regulated expression of PTEN is probably an important molecular event in tumorigenesis of ovarian cancer. Abnormal expression of PTEN gene is involved in progression of ovarian cancer. Reduced expression of PTEN gene is closely associated with tumorigenesis and pathobiological behaviors of ovarian endometrioid cancer.

Adolescent↗
PubMed2005

PTEN and p53 abnormalities are indicative and predictive factors for endometrial carcinoma.

PTEN (phosphatase and tensin homologue deleted on chromosome 10) and p53 alterations were expected to be diversely involved in endometrial carcinogenesis. Patients (n=92) with endometrial carcinoma (EC) were analyzed, and PTEN and p53 were immunostained in the tissue sections. Tumor histology, grade of differentiation, presence of endometrial hyperplasia, staining status of PTEN and p53 and clinical information were examined. There were 37 cases (40%) negative for PTEN staining, which suggests lost or reduced PTEN function. Loss of PTEN staining was significantly related to the advanced staging in the grade 1 (G1) and grade 2 (G2) endometrioid adenocarcinoma group (p=0.026). Also, 18 cases (20%) showed positive staining for p53. p53 staining was largely found in grade 3 (G3) endometrioid adenocarcinoma and other phenotypes of EC. In the G1 and G2 group, all 29 cases with reduced PTEN staining showed p53-negative staining (p=0.025). In the G3 and others group, 6 of 8 cases with reduced PTEN staining showed p53-positive staining. p53-positive staining was associated with a high probability of tumor recurrence in the G1 and G2 group (p=0.0234). In contrast, in the G3 and others group, p53-positive cases had a low probability of tumor recurrence (p=0.0473). Both PTEN and p53 staining may be good indicators of clinical stage and probability of tumor recurrence in EC. Reciprocal abnormality of p53 or PTEN occurred at an early phase of carcinogenesis, however simultaneous abnormality of p53 and PTEN often occurred at the a late phase of carcinogenesis. Thus, immunohistochemistry for PTEN and p53 in biopsy specimens of EC can provide supportive information for determining a treatment plan.

Adult↗
PubMed2005

[Effects of in vitro PTEN transfection on proliferation of human pancreatic cancer ASPC-1 cells].

OBJECTIVE: To investigate the effect of phosphatase and ensinhomology deleted on chromosome ten (PTEN) on the human pancreatic cancer cell line without or low PTEN expression. METHODS: We selected the lowest PTEN gene expressive pancreatic cancer cell line among the four pancreatic cancer cell lines (Miapaca I, Miapaca II, JF305 and ASPC-1) through RT-PCR assay method, and transfected plasmid (Peak8) inserting PTEN or not in vitro into it by lipofectin. The effect of PTEN transfection on the lowest PTEN gene expressive pancreatic cancer cell line was carried out by flow cytometry, immunohistochemical staining, cloning survival assay, as well as tumorigenicity in nude mice. RESULTS: The lowest PTEN gene expression was found in ASPC-1 cells. PTEN mRNA expression and cloning plating efficiency in the ASPC-1, A-pE and A-pE-P cells were 20.3%, 15.0%, 56.8% and 33.3%, 31.7%, 24.0% respectively. We found that ASPC-1 cells transfected with PTEN exhibited significantly more protein, less vascular endothelial growth factor protein, and non-changed epidermal growth factor receptor protein comparing with vector-transfected cells. The tumor volumes were 202.7 mm(3) and 142.4 mm(3), pre-and post-transfection with significance (P < 0.01) within 5 weeks. CONCLUSIONS: Our findings suggested that PTEN mRNA exhibited the lowest expression in ASPC-1 cell line, exogenous PTEN dramatically inhibits the growth of ASPC-1 cells transfected with PTEN gene in nude mice.

Animals↗
PubMed2006

[Expression of tumor suppressor gene PTEN in laryngeal carcinoma and its clinical significance].

OBJECTIVE: To investigate the expression of tumor suppressor gene PTEN in laryngeal carcinoma and study its clinical-pathological implication and its clinical significance. METHOD: The expression of PTEN was detected by immunohistochemistry SP(Streptavidin peroxidase) method in 68 cases of laryngeal carcinoma, 33 cases of adjacent normal laryngeal mucosa. RESULT: (1) There was 61.8% (42 of 68) of cases with expression of PTEN in the tumor tissues, and 100.0% of cases (33 of 33) with the expression of PTEN in the normal mucosa. The positive expression of PTEN in the laryngeal carcinoma gorp was remarkably lower than that in the control group. ( P <0.01). (2) The positive expression of PTEN in high and middle degree of differentiation group was significantly higher than that in low degree of differentiation(79.3% vs 48.7%). Tumors with lymph node metastases(55.0%) had less PTEN protein expression than those without metastasis(71.4%) (P <0.05). As for the PTEN expression between I + II stage and III + IV stage, the difference was significant (76.0% vs 53.5%)(P <0.05). The positive rates of PTEN decreased with clinical stage, the poor differentiation, deep invasion and lymph nodes metastasis ( P <0.05). PTEN protein expression had no relation to the patients' age, sex, tumor size and location (P >0.05). CONCLUSION: PTEN gene plays an important role in the occurrence and development of laryngeal carcinoma. It is suggested that PTEN can be a useful marker for predicting invasion and metastasis ability of laryngeal carcinoma.

Adult↗
PubMed2006

[Exogenous PTEN enhances apoptosis in pancreas cancer cell line ASPC-1 induced by hypoxia].

OBJECTIVE: To investigate the effect of exogenous phosphatase and tensin homologue deleted on chromosome ten (PTEN) on cell cycle, the expression of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) proteins, and cellular proliferation ability in human pancreas cancer cell line (ASPC-1) exposed to normal oxygen or hypoxia 1% for 24 h were determined. METHODS: ASPC-1 cells were transfected in vitro with an eukaryotic expression plasmid (pEAK8) containing PTEN or not by lipofectin. Positive cell clones were selected, amplified and named ASPC-1-pEAK8-PTEN or ASPC-1-pEAK8 cells. RT-PCR and Western blot were used to determine the target gene expression. PTEN, VEGF and EGFR proteins were assessed by Western blot assay. Cell cycle and the induction of apoptosis were detected by flow cytometry. The tumor growth ability in vivo was assessed in nude mice, and cologenic survival ability was assayed under normal oxygen or hypoxia condition. RESULTS: The expression of PTEN mRNA and protein in ASPC-1-pEAK8-PTEN cells were significantly higher than that in ASPC-1-pEAK8 or ASPC-1 cells. The expression of VEGF protein in ASPC-1-pEAK8-PTEN cells decreased by 23.4%, but EGFR showed no change. The plating efficiency was decreased by 28.0% (F = 4.283, P < 0.05) under normal oxygen condition, compared with those in ASPC-1 cells. The tumor volume in nude mice with ASPC-1-pEAK8-PTEN were significantly different compared to those with ASPC-1 5 weeks after implantation (t = 4.834, P < 0.01). The tumor inhibitory rate was 42.4% in ASPC-1-pEAK8-PTEN group. The expressions of VEGF and EGFR were decreased by 31.4% and 25.0%, respectively. In comparison with ASPC-1 cells, the plating efficiency of ASPC-1-pEAK8-PTEN cells was decreased by 33.2% (F = 9.152, P < 0.01) under hypoxic condition. The cellular apoptosis 8 h after hypoxia and G(2)/M blockage in ASPC-1-pEAK8-PTEN cells were remarkably higher than those in ASPC-1 cells. CONCLUSION: Exogenous PTEN can block ASPC-1 cell cycle at the G(2)/M phase, enhance the cell apoptosis induced by hypoxia, inhibit the expression of VEGF and EGFR proteins under hypoxic condition, and inhibit the proliferation and growth of ASPC-1 cells.

Animals↗
PubMed1999

Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: differential involvement of focal adhesion kinase and p130Cas.

PTEN/MMAC1 is a major new tumor suppressor gene that encodes a dual-specificity phosphatase with sequence similarity to the cytoskeletal protein tensin. Recently, we reported that PTEN dephosphorylates focal adhesion kinase (FAK) and inhibits cell migration, spreading, and focal adhesion formation. Here, the effects of PTEN on cell invasion, migration, and growth as well as the involvement of FAK and p130 Crk-associated substrate (p130Cas) were investigated in U87MG glioblastoma cells missing PTEN. Cell invasion, migration, and growth were down-regulated by expression of phosphatase-active forms of PTEN but not by PTEN with an inactive phosphatase domain; these effects were correlated with decreased tyrosine phosphorylation levels of FAK and p130Cas. Overexpression of FAK concomitant with PTEN resulted in increased total tyrosine phosphorylation levels of FAK and p130Cas and effectively antagonized the effects of PTEN on cell invasion and migration and partially on cell growth. Overexpression of p130Cas increased total tyrosine phosphorylation levels of p130Cas without affecting those of FAK; however, although p130Cas could reverse PTEN inhibition of cell invasion and migration, it did not rescue cell growth in U87MG cells. In contrast to FAK, p130Cas could not be shown to interact with PTEN in cells, and it was not dephosphorylated directly by PTEN in vitro. These results suggest important roles of PTEN in the phenotype of tumor progression, and that the effects of PTEN on cell invasion, migration, and growth are mediated by distinct downstream pathways that diverge at the level of FAK.

Cell Adhesion Molecules↗