The Mechanisms Underlying PTEN Loss in Human Tumors Suggest Potential Therapeutic Opportunities

Chang, Hyeyoun; Cai, Zhenying; Roberts, Thomas M.

doi:10.3390/biom9110713

Cited by 22 publications

(18 citation statements)

References 187 publications

(218 reference statements)

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“…Overall, we would expect differences affecting hotspots or signatures to be minor, but in the absence of a rigorous analysis of sufficiently large datasets in the existing literature, it is not possible to make a definitive statement. In addition, PTEN expression is also subject to epigenetic controls 83 , which include promoter hypermethylation (particularly in MT-H tumors 84 ) and targeting by microRNAs 85 ; information bearing on the impact of these epigenetic control mechanisms is not available for the specimens analyzed here. However, based on the size of the dataset analyzed here, our study provides a detailed blueprint for segregating CRC tumors by PTEN mutation status within the landscape of various clinical subgroups and co-mutation patterns, providing context for subsequent analysis of epigenetic control of PTEN expression, and helping to enable rational design of future treatment combinations.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive characterization of PTEN mutational profile in a series of 34,129 colorectal cancers

et al. 2022

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Loss of expression or activity of the tumor suppressor PTEN acts similarly to an activating mutation in the oncogene PIK3CA in elevating intracellular levels of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), inducing signaling by AKT and other pro-tumorigenic signaling proteins. Here, we analyze sequence data for 34,129 colorectal cancer (CRC) patients, capturing 3,434 PTEN mutations. We identify specific patterns of PTEN mutation associated with microsatellite stability/instability (MSS/MSI), tumor mutational burden (TMB), patient age, and tumor location. Within groups separated by MSS/MSI status, this identifies distinct profiles of nucleotide hotspots, and suggests differing profiles of protein-damaging effects of mutations. Moreover, discrete categories of PTEN mutations display non-identical patterns of co-occurrence with mutations in other genes important in CRC pathogenesis, including KRAS, APC, TP53, and PIK3CA. These data provide context for clinical targeting of proteins upstream and downstream of PTEN in distinct CRC cohorts.

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Section: Discussionmentioning

confidence: 99%

Comprehensive characterization of PTEN mutational profile in a series of 34,129 colorectal cancers

et al. 2022

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“…Loss-of-function mutations or suppression of PTEN drives the development of diverse human cancers, including NSCLC [ 39 , 40 ]. PI3K signaling is one of the most crucial pathways in cancer biology, regulating cell cycle progression, survival, migration, invasion, and metabolism of cancer cells, and PTEN is the main negative regulator of it by dephosphorylating PIP 3 to PIP 2 [ 39 , 40 ]. PTEN also regulates chromosome stability, DNA repair, and apoptosis as a protein phosphatase [ 39 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

“…PI3K signaling is one of the most crucial pathways in cancer biology, regulating cell cycle progression, survival, migration, invasion, and metabolism of cancer cells, and PTEN is the main negative regulator of it by dephosphorylating PIP 3 to PIP 2 [ 39 , 40 ]. PTEN also regulates chromosome stability, DNA repair, and apoptosis as a protein phosphatase [ 39 , 40 ]. PTEN mutations are frequent in different cancer types; besides, PTEN expression is down-regulated at both transcriptional and post-transcriptional levels.…”

Section: Discussionmentioning

confidence: 99%

Circular RNA circ_0001287 inhibits the proliferation, metastasis, and radiosensitivity of non-small cell lung cancer cells by sponging microRNA miR-21 and up-regulating phosphatase and tensin homolog expression

Zhang

Feng

et al. 2021

Bioengineered

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As a type of non-coding RNA, circular RNA (circRNA) figures prominently in human cancer progression. Nonetheless, the expression, function, and regulatory mechanism of circ_0001287 in non-small cell lung cancer (NSCLC) remain obscure. In this work, quantitative real-time polymerase chain reaction (qRT-PCR) was implemented to quantify circ_0001287 and miR-21 expressions in NSCLC tissues and cells. The relationship between circ_0001287 expression and the clinicopathological parameters of NSCLC patients was examined. Cell counting kit-8 (CCK-8), 5-bromo-2©-deoxyuridine (BrdU), and Transwell experiments were conducted to detect the multiplication, migration, and invasion of NSCLC cells after circ_0001287 was overexpressed or knocked down. The survival of NSCLC cells was studied using colony formation experiment under different doses of radiation. RNA immunoprecipitation (RIP) experiment and luciferase reporter gene experiment verified the binding relationship between circ_0001287 and miR-21. Western blot was employed to examine the regulatory effects of circ_0001287 and miR-21 on phosphatase and tensin homolog (PTEN) expression. We reported that circ_0001287 expression was down-modulated in NSCLC tissues and cell lines. Besides, circ_0001287 low expression was associated with low differentiation and positive lymph node invasion of NSCLC. Circ_0001287 overexpression suppressed the multiplication, migration, invasion, and radioresistance of NSCLC cells, whereas circ_0001287 knockdown promoted the above phenotypes. Circ_0001287 could adsorb miR-21 and repress its expression, and indirectly up-modulate PTEN expression in NSCLC cells. Taken together, circ_0001287/miR-21/PTEN axis is probably involved in regulating NSCLC cell multiplication, metastasis, and radioresistance.

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“…PI3K phosphorylates and activates AKT, resulting in effects such as p21 stabilisation to aid survival [121] and MDM2 localisation to the nucleus to inhibit p53 [122]. The PI3K/AKT pathway is inhibited by PTEN (phosphatase and tensin homologue) [123][124][125], an important tumour suppressor [126]. Studies of acute lymphoblastic leukaemia (ALL) revealed that nutlin-3 upregulated p53 in all wild-type p53 cells, but apoptosis was induced only in PTEN-positive cells.…”

Section: Pi3k/akt Pten Mtor and Autophagymentioning

confidence: 99%

Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?

et al. 2021

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Since the discovery of the first MDM2 inhibitors, we have gained deeper insights into the cellular roles of MDM2 and p53. In this review, we focus on MDM2 inhibitors that bind to the p53-binding domain of MDM2 and aim to disrupt the binding of MDM2 to p53. We describe the basic mechanism of action of these MDM2 inhibitors, such as nutlin-3a, summarise the determinants of sensitivity to MDM2 inhibition from p53-dependent and p53-independent points of view and discuss the problems with innate and acquired resistance to MDM2 inhibition. Despite progress in MDM2 inhibitor design and ongoing clinical trials, their broad use in cancer treatment is not fulfilling expectations in heterogenous human cancers. We assess the MDM2 inhibitor types in clinical trials and provide an overview of possible sources of resistance to MDM2 inhibition, underlining the need for patient stratification based on these aspects to gain better clinical responses, including the use of combination therapies for personalised medicine.

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The Mechanisms Underlying PTEN Loss in Human Tumors Suggest Potential Therapeutic Opportunities

Cited by 22 publications

References 187 publications

Comprehensive characterization of PTEN mutational profile in a series of 34,129 colorectal cancers

Comprehensive characterization of PTEN mutational profile in a series of 34,129 colorectal cancers

Circular RNA circ_0001287 inhibits the proliferation, metastasis, and radiosensitivity of non-small cell lung cancer cells by sponging microRNA miR-21 and up-regulating phosphatase and tensin homolog expression

Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?

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