scholarly journals PTEN as a Prognostic/Predictive Biomarker in Cancer: An Unfulfilled Promise?

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 435 ◽  
Author(s):  
Chiara Bazzichetto ◽  
Fabiana Conciatori ◽  
Matteo Pallocca ◽  
Italia Falcone ◽  
Maurizio Fanciulli ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Predictive Biomarker ◽  
Suppressor Gene ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatase And Tensin Homolog ◽  
Cell Functions ◽  
Tensin Homolog ◽  
Personalized Cancer Therapy ◽  
And Function ◽  
Personalized Cancer

Identifying putative biomarkers of clinical outcomes in cancer is crucial for successful enrichment, and for the selection of patients who are the most likely to benefit from a specific therapeutic approach. Indeed, current research in personalized cancer therapy focuses on the possibility of identifying biomarkers that predict prognosis, sensitivity or resistance to therapies. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene that regulates several crucial cell functions such as proliferation, survival, genomic stability and cell motility through both enzymatic and non-enzymatic activities and phosphatidylinositol 3-kinase (PI3K)-dependent and -independent mechanisms. Despite its undisputed role as a tumor suppressor, assessment of PTEN status in sporadic human tumors has yet to provide clinically robust prognostic, predictive or therapeutic information. This is possibly due to the exceptionally complex regulation of PTEN function, which involves genetic, transcriptional, post-transcriptional and post-translational events. This review shows a brief summary of the regulation and function of PTEN and discusses its controversial aspects as a prognostic/predictive biomarker.

scholarly journals PTENSequence Analysis in Endometrial Hyperplasia and Endometrial Carcinoma in Slovak Women

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
H. Gbelcová ◽  
P. Bakeš ◽  
P. Priščáková ◽  
V. Šišovský ◽  
I. Hojsíková ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Endometrial Carcinoma ◽  
Endometrial Hyperplasia ◽  
Female Genital Tract ◽  
Suppressor Gene ◽  
Serous Carcinoma ◽  
Tissue Samples ◽  
Phosphatase And Tensin Homolog ◽  
Coding Regions ◽  
Tensin Homolog

Phosphatase and tensin homolog (PTEN) is a protein that acts as a tumor suppressor by dephosphorylating the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate. Loss of PTEN function has been implicated in the pathogenesis of a number of different tumors, particularly endometrial carcinoma (ECa). ECa is the most common neoplasia of the female genital tract. Our study evaluates an association between the morphological appearance of endometrial hyperplasia and endometrial carcinoma and the degree ofPTENalterations. A total of 45 endometrial biopsies from Slovak women were included in present study. Formalin-fixed and paraffin-embedded tissue samples with simple hyperplasia (3), complex hyperplasia (5), atypical complex hyperplasia (7), endometrioid carcinomas G1 (20) and G3 (5), and serous carcinoma (5) were evaluated for the presence of mutations in coding regions ofPTENgene, the most frequently mutated tumor suppressor gene in endometrial carcinoma. 75% of the detected mutations were clustered in exons 5 and 8. Out of the 39 mutations detected in 24 cases, 20 were frameshifts and 19 were nonsense, missense, or silent mutations. Some specimens harboured more than one mutation. The results of current study on Slovak women were compared to a previous study performed on Polish population. The two sets of results were similar.

scholarly journals Immunohistochemical Characterization of Phosphorylated Ubiquitin in the Mouse Hippocampus

2020 ◽  
Author(s):  
Kosuke Kataoka ◽  
Andras Bilkei-Gorzo ◽  
Andreas Zimmer ◽  
Toru Asahi
Keyword(s):  
Cell Layer ◽  
Granule Cell Layer ◽  
Phosphatase And Tensin Homolog ◽  
Neuronal Markers ◽  
Tensin Homolog ◽  
Evolutionarily Conserved ◽  
Previous Hypothesis ◽  
Mouse Hippocampus ◽  
And Function

ABSTRACTMitochondrial autophagy (mitophagy) is an essential and evolutionarily conserved process that maintains mitochondrial integrity via the removal of damaged or superfluous mitochondria in eukaryotic cells. Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and Parkin promote mitophagy and function in a common signaling pathway. PINK1-mediated ubiquitin phosphorylation at Serine 65 (Ser65-pUb) is a key event in the efficient execution of PINK1/Parkin-dependent mitophagy. However, few studies have used immunohistochemistry to analyze Ser65-pUb in the mouse. Here, we examined the immunohistochemical characteristics of Ser65-pUb in the mouse hippocampus. Some hippocampal cells were Ser65-pUb positive, whereas the remaining cells expressed no or low levels of Ser65-pUb. PINK1 deficiency resulted in a decrease in the density of Ser65-pUb-positive cells, consistent with a previous hypothesis based on in vitro research. Interestingly, Ser65-pUb-positive cells were detected in hippocampi lacking PINK1 expression. The CA3 pyramidal cell layer and the dentate gyrus (DG) granule cell layer exhibited significant reductions in the density of Ser65-pUb-positive cells in PINK1-deficient mice. Moreover, Ser65-pUb immunoreactivity colocalized predominantly with neuronal markers. These findings suggest that Ser65-pUb may serve as a biomarker of in situ PINK1 signaling in the mouse hippocampus; however, the results should be interpreted with caution, as PINK1 deficiency downregulated Ser65-pUb only partially.

scholarly journals Phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog as therapeutic targets in breast cancer

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769552 ◽  
Author(s):  
Ebubekir Dirican ◽  
Mustafa Akkiprik
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Breast Cancer Progression ◽  
Regulatory Subunit ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Kinase Pathway ◽  
Phosphatidylinositol 3

Breast cancer is the most commonly diagnosed cancer among women in Turkey and worldwide. It is considered a heterogeneous disease and has different subtypes. Moreover, breast cancer has different molecular characteristics, behaviors, and responses to treatment. Advances in the understanding of the molecular mechanisms implicated in breast cancer progression have led to the identification of many potential therapeutic gene targets, such as Breast Cancer 1/2, phosphatidylinositol 3-kinase catalytic subunit alpha, and tumor protein 53. The aim of this review is to summarize the roles of phosphatidylinositol 3-kinase regulatory subunit 1 (alpha) (alias p85α) and phosphatase and tensin homolog in breast cancer progression and the molecular mechanisms involved. Phosphatase and tensin homolog is a tumor suppressor gene and protein. Phosphatase and tensin homolog antagonizes the phosphatidylinositol 3-kinase/AKT signaling pathway that plays a key role in cell growth, differentiation, and survival. Loss of phosphatase and tensin homolog expression, detected in about 20%–30% of cases, is known to be one of the most common tumor changes leading to phosphatidylinositol 3-kinase pathway activation in breast cancer. Instead, the regulatory subunit p85α is a significant component of the phosphatidylinositol 3-kinase pathway, and it has been proposed that a reduction in p85α protein would lead to decreased negative regulation of phosphatidylinositol 3-kinase and hyperactivation of the phosphatidylinositol 3-kinase pathway. Phosphatidylinositol 3-kinase regulatory subunit 1 protein has also been reported to be a positive regulator of phosphatase and tensin homolog via the stabilization of this protein. A functional genetic alteration of phosphatidylinositol 3-kinase regulatory subunit 1 that results in reduced p85α protein expression and increased insulin receptor substrate 1 binding would lead to enhanced phosphatidylinositol 3-kinase signaling and hence cancer development. Phosphatidylinositol 3-kinase regulatory subunit 1 underexpression was observed in 61.8% of breast cancer samples. Therefore, expression/alternations of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog genes have crucial roles for breast cancer progression. This review will summarize the biological roles of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog in breast cancer, with an emphasis on recent findings and the potential of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog as a therapeutic target for breast cancer therapy.

scholarly journals The PTEN Tumor Suppressor Gene in Soft Tissue Sarcoma

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1169 ◽  
Author(s):  
Sioletic Stefano ◽  
Scambia Giovanni
Keyword(s):  
Soft Tissue ◽  
Tumor Suppressor ◽  
Soft Tissue Sarcoma ◽  
Biological Significance ◽  
Treatment Strategies ◽  
Predictive Biomarkers ◽  
Suppressor Gene ◽  
Oncogenic Signaling ◽  
Tensin Homolog ◽  
Pathologic Features

Soft tissue sarcoma (STS) is a rare malignancy of mesenchymal origin classified into more than 50 different subtypes with distinct clinical and pathologic features. Despite the poor prognosis in the majority of patients, only modest improvements in treatment strategies have been achieved, largely due to the rarity and heterogeneity of these tumors. Therefore, the discovery of new prognostic and predictive biomarkers, together with new therapeutic targets, is of enormous interest. Phosphatase and tensin homolog (PTEN) is a well-known tumor suppressor that commonly loses its function via mutation, deletion, transcriptional silencing, or protein instability, and is frequently downregulated in distinct sarcoma subtypes. The loss of PTEN function has consequent alterations in important pathways implicated in cell proliferation, survival, migration, and genomic stability. PTEN can also interact with other tumor suppressors and oncogenic signaling pathways that have important implications for the pathogenesis in certain STSs. The aim of the present review is to summarize the biological significance of PTEN in STS and its potential role in the development of new therapeutic strategies.

scholarly journals BMI1 promotes cardiac fibrosis in ischemia-induced heart failure via the PTEN-PI3K/Akt-mTOR signaling pathway

2019 ◽  
Vol 316 (1) ◽  
pp. H61-H69 ◽  
Author(s):  
Wenbo Yang ◽  
Zhijun Wu ◽  
Ke Yang ◽  
Yanxin Han ◽  
Yanjia Chen ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Mammalian Target Of Rapamycin ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatase And Tensin Homolog ◽  
B Lymphoma ◽  
Tensin Homolog ◽  
And Migration ◽  
Proliferation And Migration

Cardiac fibrosis has been known to play an important role in the etiology of heart failure after myocardial infarction (MI). B lymphoma Mo-MLV insertion region 1 homolog (BMI1), a transcriptional repressor, is important for fibrogenesis in the kidneys. However, the effect of BMI1 on ischemia-induced cardiac fibrosis remains unclear. BMI1 was strongly expressed in the infarct region 1 wk post-MI in mice and was detected by Western blot and histological analyses. Lentivirus-mediated overexpression of BMI1 significantly promoted cardiac fibrosis, worsened cardiac function 4 wk after the intervention in vivo, and enhanced the proliferation and migration capabilities of fibroblasts in vitro , whereas downregulation of BMI1 decreased cardiac fibrosis and prevented cardiac dysfunction in mice 4 wk post-MI in vivo. Furthermore, upregulated BMI1 inhibited phosphatase and tensin homolog (PTEN) expression, enhanced phosphatidylinositol 3-kinase (PI3K) expression, and increased the phosphorylation level of Akt and mammalian target of rapamycin (mTOR) in mice 4 wk after lentiviral infection, which was in accordance with the changes seen in their infarcted myocardial tissues. At the same time, the effects of BMI1 on cardiac fibroblasts were reversed in vitro when these cells were exposed to NVP-BEZ235, a dual-kinase (PI3K/mTOR) inhibitor. In conclusion, BMI1 is associated with cardiac fibrosis and dysfunction after MI by regulating cardiac fibroblast proliferation and migration, and these effects could be partially explained by the regulation of the PTEN-PI3K/Akt-mTOR pathway. NEW & NOTEWORTHY Ischemia-induced B lymphoma Mo-MLV insertion region 1 homolog (BMI1) significantly promoted cardiac fibrosis and worsened cardiac function in vivo, whereas downregulation of BMI1 decreased cardiac fibrosis and prevented cardiac dysfunction in myocardial infarcted mice. BMI1 also enhanced proliferation and migration capabilities of fibroblasts in vitro; these effects were reversed by NVP-BEZ235. Effects of BMI1 on cardiac fibrosis could be partially explained by regulation of the phosphatase and tensin homolog-phosphatidylinositol 3-kinase/Akt-mammalian target of rapamycin pathway.

Characterization of tumor mutation load (TML) in solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11517-11517 ◽  
Author(s):  
Mohamed E. Salem ◽  
Joanne Xiu ◽  
Heinz-Josef Lenz ◽  
Michael B. Atkins ◽  
Philip Agop Philip ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Gene Mutations ◽  
Predictive Biomarker ◽  
Suppressor Gene ◽  
Older Age ◽  
Patient Treatment ◽  
Missense Mutations ◽  
Driver Genes ◽  
Primary Nsclc ◽  
The Impact

11517 Background: Rapid advances in immunotherapy have created a need for biomarkers to improve patient treatment selection. TML is proposed as a potential predictive biomarker due to its association with tumor immunogenicity. Methods: TML was assessed in 8020 tumors from 14 different cancers using somatic nonsynonymous missense mutations sequenced with a 592-gene panel. High TML was set at ≥ 17 mutations per megabase (mt/MB) based on an established concordance ( > 99%) with MSI-High in colorectal cancer (CRC). Results: Mean TML was highest in melanoma (Mel; 21 mt/MB), NSCLC (11 mt/MB), and bladder cancer (BLC; 11 mt/MB), whereas prostate cancer (PC), pancreas adenocarcinoma (PA), and renal cell carcinoma (RCC) had the lowest levels (all 6 mt/MB). High TML was seen most frequently in Mel (36%), NSCLC (15%), BLC (15%), and anal cancer (SCCA; 9%); and least frequently in PA (1.6%) and RCC (0.5%). Primary NSCLC carried lower TML than its brain metastases (11 vs. 16 mt/MB, p < 0.001). Older age was associated with higher TML in Mel (p = 0.001), CRC (p = 0.009), breast cancer (BC; p = 0.01), and NSCLC (p = 0.02). Higher TML was seen in males than in females for Mel (p = 0.002) and NSCLC (p < 0.001). Presence of mutations in oncogenic driver genes such as EGFR, ALK, ROS1 RET fusions, cMET exon 14 skipping correlated with lower TML in NSCLC (6.9 vs. 12 mt/MB, p < 0.001), as did BRAF and NRAS mutations in Mel (17 vs. 26, p = 0.003). Conversely, mutations in tumor suppressor genes such as ARID1A (CRC, NSCLC, and BLC) and NF1 (BC, CRC, Mel, BLC, and NSCLC) were associated with higher TML (p < 0.05). MSI-high was correlated with high TML in CRC and gastric cancers (p < 0.05). Conclusions: TML varied significantly among different cancers. High TML was associated with older age, absence of oncogenic mutations and presence of tumor suppressor gene mutations. Future studies will assess the impact of TML on clinical outcome and establish its role in selecting patients for immunotherapy. [Table: see text]

scholarly journals Molecular Analysis of AFP and HSA Interactions with PTEN Protein

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Mingyue Zhu ◽  
Bo Lin ◽  
Peng Zhou ◽  
Mengsen Li
Keyword(s):  
Molecular Docking ◽  
Molecular Mechanisms ◽  
Docking Study ◽  
Phosphatidylinositol 3 Kinase ◽  
Molecular Docking Study ◽  
Pten Protein ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Significant Homology ◽  
Modeling Data

Human cytoplasmic alpha-fetoprotein (AFP) has been classified as a member of the albuminoid gene family. The protein sequence of AFP has significant homology to that of human serum albumin (HSA), but its biological characteristics are vastly different from HSA. The AFP functions as a regulator in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway, but HSA plays a key role as a transport protein. To probe their molecular mechanisms, we have applied colocalization, coimmunoprecipitation (co-IP), and molecular docking approaches to analyze the differences between AFP and HSA. The data from colocalization and co-IP displayed a strong interaction between AFP and PTEN (phosphatase and tensin homolog), demonstrating that AFP did bind to PTEN, but HSA did not. The molecular docking study further showed that the AFP domains I and III could contact with PTEN.In siliconsubstitutions of AFP binding site residues at position 490M/K and 105L/R corresponding to residues K490 and R105 in HSA resulted in steric clashes with PTEN residues R150 and K46, respectively. These steric clashes may explain the reason why HSA cannot bind to PTEN. Ultimately, the experimental results and the molecular modeling data from the interactions of AFP and HSA with PTEN will help us to identify targets for designing drugs and vaccines against human hepatocellular carcinoma.

scholarly journals Phosphatase and Tensin Homolog in Non-neoplastic Digestive Disease: More Than Just Tumor Suppressor

2021 ◽  
Vol 12 ◽  
Author(s):  
Tianyu He ◽  
Xiaoyun Zhang ◽  
Jianyu Hao ◽  
Shigang Ding
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Malignant Tumors ◽  
Biological Effects ◽  
Pten Protein ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Lipid Phosphatase ◽  
And Migration

The Phosphatase and tensin homolog (PTEN) gene is one of the most important tumor suppressor genes, which acts through its unique protein phosphatase and lipid phosphatase activity. PTEN protein is widely distributed and exhibits complex biological functions and regulatory modes. It is involved in the regulation of cell morphology, proliferation, differentiation, adhesion, and migration through a variety of signaling pathways. The role of PTEN in malignant tumors of the digestive system is well documented. Recent studies have indicated that PTEN may be closely related to many other benign processes in digestive organs. Emerging evidence suggests that PTEN is a potential therapeutic target in the context of several non-neoplastic diseases of the digestive tract. The recent discovery of PTEN isoforms is expected to help unravel more biological effects of PTEN in non-neoplastic digestive diseases.

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