Coalterations of p53 and PTEN tumor suppressor genes in non–small cell lung carcinoma patients

Andjelković, Tijana; Banković, Jasna; Stojšić, Jelena; Milinkovic, Vedrana; Podolski-Renić, Ana; Ruždijić, Sabera; Tanić, Nikola

doi:10.1016/j.trsl.2010.09.004

Cited by 25 publications

(16 citation statements)

References 39 publications

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“…The subsequent acquisition of a PTEN haploinsufficiency in benign prostatic precursors may be specific for prostate cancer (Hill et al, 2005;Zhong et al, 2006), as other tumor types favor point mutations and small deletions within the PTEN locus as a preferred mechanism of PTEN inactivation (Guo et al, 2008;Heald et al, 2010;Andjelkovic et al, 2011;Xu et al, 2011). Reduced PTEN protein levels may facilitate genomic instability, leading to the acquisition of other genomic rearrangements.…”

Section: Discussionmentioning

confidence: 99%

PTEN genomic deletions that characterize aggressive prostate cancer originate close to segmental duplications

Yoshimoto

Ludkovski

DeGrace

et al. 2011

Genes Chromosomes & Cancer

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Deletion of PTEN at 10q23.3 occurs in ∼40% of human prostate cancers and is associated with aggressive metastatic potential, poor prognosis, and androgen-independence. This high frequency of recurrent PTEN deletions in prostate cancer suggests there may be unusual genomic features close to this locus that facilitate DNA alteration at 10q23.3. To explore possible mechanisms for deletions in the PTEN region, a meta-analysis of 311 published human genome array datasets was conducted and determined that the minimal prostate cancer-associated deletion at 10q23.3 corresponds to ∼2.06 MB region flanked by BMPR1A and FAS. On a separate cohort comprising an additional 330 tumors, four-color fluorescence in situ hybridization analysis using probes for BMPR1A, FAS, cen(10), and PTEN showed that 132 of 330 (40%) tumors had PTEN loss, 50 (15%) of which were homozygous losses (comprising in total 100 deletion events). Breakpoints between PTEN and BMPR1A or FAS were subsequently mapped in 100 homozygous and 82 hemizygous PTEN losses, revealing that 125/182 PTEN microdeletions occurred within the 940 kB interval between BMPR1A and PTEN. Furthermore, this breakpoint interval coincides with a repeat-rich region of 414 kB containing the SD17 and SD18 segmental duplications, which contain at least 13 homologous inverted repeat sequences. Together, these data suggest that a strong selective growth advantage for loss of PTEN and upregulation of PI3K/AKT, combined with the close proximity of PTEN to a large unstable segment of repeated DNA comprising SD17 and SD18, can lead to recurrent microdeletions of the PTEN gene in prostate cancer. © 2011 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

PTEN genomic deletions that characterize aggressive prostate cancer originate close to segmental duplications

Yoshimoto

Ludkovski

DeGrace

et al. 2011

Genes Chromosomes & Cancer

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“…Diagnosis of NSCLC, the histological grade, stage, necrosis, and lymph node invasion were established by histological analyses of the surgical specimens. All specimens had been subjected to an earlier analysis, and their distribution by relevant clinicopathological parameters was given in a previous publication [16]. Neither pre-surgical chemotherapy nor radiotherapy had been administered.…”

Section: Tissue Samplesmentioning

confidence: 99%

“…Genetic and epigenetic alterations of PTEN tumor suppressor gene were analyzed in our previous publication [16]. To summarize, PTEN was tested for the existence of loss of heterozygosity (LOH) and hypermethylation of its promoter.…”

Section: Analysis Of Alterations In Pten Tumor Suppressor Genementioning

confidence: 99%

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Association of CCND1 overexpression with KRAS and PTEN alterations in specific subtypes of non-small cell lung carcinoma and its influence on patients’ outcome

et al. 2015

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Cyclin D1 is one of the major cellular oncogenes, overexpressed in number of human cancers, including non-small cell lung carcinoma (NSCLC). However, it does not exert tumorigenic activity by itself, but rather cooperates with other altered oncogenes and tumor suppressors. Therefore, in the present study, we have examined mutual role of cyclin D1, KRAS, and PTEN alterations in the pathogenesis of NSCLC and their potential to serve as multiple molecular markers for this disease. CCND1 gene amplification and gene expression were analyzed in relation to mutational status of KRAS gene as well as to PTEN alterations (loss of heterozygosity and promoter hypermethylation) in NSCLC patient samples. Moreover, the effect of these co-alterations on patient survival was examined. Amplified CCND1 gene was exclusively associated with increased gene expression. Statistical analyses also revealed significant association between CCND1 overexpression and KRAS mutations in the whole group and in the groups of patients with adenocarcinoma, grade 1/2, and stage I/II. In addition, CCND1 overexpression was significantly related to PTEN promoter hypermethylation in the whole group and in the group of patients with squamous cell carcinoma and lymph node invasion. These joint alterations also significantly shortened patients' survival and were shown to be an independent factor for adverse prognosis. Overall results point that cyclin D1 expression cooperates with KRAS and PTEN alterations in pathogenesis of NSCLC, and they could serve as potential multiple molecular markers for specific subgroups of NSCLC patients as well as prognostic markers for this type of cancer.

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“…The inhibition of one of these processes can substantially prevent secondary tumors from spreading in the body [3,4] . The tumor suppressor protein, which functions in cell cycle regulation, apoptosis induction, DNA damage repair, and metastasis inhibition, is a potential therapeutic target in lung cancer [5][6][7] . One of the promising examples is p53, whose mutation has been detected in 90% of small cell lung cancers and in 50% of non-small cell lung cancer.…”

Section: Introductionmentioning

confidence: 99%

Suppression of human lung cancer cell proliferation and metastasis in vitro by the transducer of ErbB-2.1 (TOB1)

et al. 2011

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Aim: To investigate the effects of the transducer of ErbB-2.1 (TOB1) on the proliferation, migration and invasion of human lung cancer cells in vitro. Methods: Human lung cancer cell lines (95-D, A549, NCI-H1299, NCI-H1975, NCI-H661, NCI-H446, NCI-H1395, and Calu-3) and the normal human bronchial epithelial (HBE) cell line were tested. The expression levels of TOB1 in the cells were determined with Western blot and RT-PCR analyses. TOB1-overexpressing cell line 95-D/TOB1 was constructed using lipofectamine-induced TOB1 recombinant plasmid transfection and selective G418 cell culture. The A549 cells were transcend-transfected with TOB1-siRNA. MTT assay, flow cytometry and Western blot analysis were used to examine the effects of TOB1 on cancer cell proliferation and wound healing. Transwell invasive assay was performed to evaluate the effects of TOB1 on cancer cell migration and invasion. The activity of MMP2 and MMP9 was measured using gelatin zymography assay. Results: The expression levels of TOB1 in the 8 human lung cancer cell lines were significantly lower than that in HBE cells. TOB1 overexpression inhibited the proliferation of 95-D cells, whereas TOB1 knockdown with TOB1-siRNA promoted the growth of A549 cells. Decreased cell migration and invasion were detected in 95-D/TOB1 cells, and the suppression of TOB1 enhanced the metastasis in A549 cells. TOB1 overexpression not only increased the expression of the phosphatase and tensin homolog (PTEN), an important tumor suppressor, but also regulated the downstream effectors in the PI3K/PTEN signaling pathway, including Akt, ERK1/2, etc. In contrast, decreased expression of TOB1 oppositely regulated the expression of these factors. TOB1 also regulates the gelatinase activity of MMP2 and MMP9 in lung cancer cells. Conclusion:The results demonstrate that the PI3K/PTEN pathway, which is essential for carcinogenesis, angiogenesis, and metastasis, may be one of the possible signaling pathways for regulation of proliferation and metastasis of human lung cancer cells by TOB1 in vitro.

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Coalterations of p53 and PTEN tumor suppressor genes in non–small cell lung carcinoma patients

Cited by 25 publications

References 39 publications

PTEN genomic deletions that characterize aggressive prostate cancer originate close to segmental duplications

PTEN genomic deletions that characterize aggressive prostate cancer originate close to segmental duplications

Association of CCND1 overexpression with KRAS and PTEN alterations in specific subtypes of non-small cell lung carcinoma and its influence on patients’ outcome

Suppression of human lung cancer cell proliferation and metastasis in vitro by the transducer of ErbB-2.1 (TOB1)

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