The Par-4/PTEN connection in tumor suppression
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Tumor suppressors function in a coordinated regulatory network, and their inactivation is a key step in carcinogenesis. The tumor suppressor Par-4 is a novel integral player in the PTEN network. Thus, Par-4 is absent in a high percentage of human prostate carcinomas, and its loss is concomitantly associated with PTEN loss. Genetic ablation of Par-4 induces fully invasive prostate carcinomas in PTEN-heterozygous mice. In contrast, Par-4 deficiency alone, like PTEN heterozygosis, results in lesions that are unable to progress beyond the benign neoplastic stage known as PIN. At this PIN transition, the mutual induction of Par-4 and PTEN is an additional regulatory step in preventing cancer progression. Par-4 deficiency cooperates with PTEN haploinsufficiency in prostate cancer initiation and progression and their simultaneous inactivation, in addition to enhancing Akt activation, sets in motion a unique mechanism involving the synergistic activation of NF-κB. These results suggest that the concurrent interruption of complementary signaling pathways targeting PI3K/Akt and NF-κB activation could provide new and effective strategies for cancer therapy.Keywords:
Haploinsufficiency
Tumor progression
Gallbladder carcinoma (GBC) is a highly lethal malignancy of the gastrointestinal tract. Despite extensive research, the underlying molecular mechanism of GBC remains largely unclear. Deleted in malignant brain tumors 1 (DMBT1) is low-expression during cancer progression and as a potential tumor-suppressor gene in various types of cancer. However, its role in Gallbladder cancer remains poorly understood. Here, we found that DMBT1 was significantly low-expression and deletion of copy number in GBC tissues by qRT-PCR and Western blot. Overexpression of DMBT1 impaired survival, promoted apoptosis in GBC cells in vitro, and inhibited tumor progression in vivo. Further study of underlying mechanisms demonstrated that DMBT1 combined with PTEN which could stabilize PTEN protein, resulting in inhibiting the activation of PI3K/AKT signaling pathway. Our study revealed a new sight of DMBT1 as a tumor-suppressor gene on the PI3K/AKT pathway in GBC, which may be a potential therapeutic target for improving treatment.
Gallbladder Cancer
Tumor progression
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PTEN(phosphatase and tensin homolog deleted on chromosome ten)is phosphatase specificity and can inhibit oncogenesis.The mutation and loss of PTEN is the oncogenesis basis of all kinds of tumor,including urinary system tumor.Studies show that mutation and loss of PTEN,which can lead to the dysfunction of tumor suppress,induced oncogenesis of renal cell carcinoma,bladder carcinoma and prostatic carcinoma,revealling that PTEN can inhibit tumorigenesis of urnary system.But the detail of the mutation and loss of PTEN and how PTEN inhibit tumorigensis are still unclear,further study is warranted.
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Abstract Understanding remains incomplete of the mechanisms underlying initiation and progression of prostate cancer, the most commonly diagnosed cancer in American men. The transcription factor SOX4 is overexpressed in many human cancers, including prostate cancer, suggesting it may participate in prostate tumorigenesis. In this study, we investigated this possibility by genetically deleting Sox4 in a mouse model of prostate cancer initiated by loss of the tumor suppressor Pten. We found that specific homozygous deletion of Sox4 in the adult prostate epithelium strongly inhibited tumor progression initiated by homozygous loss of Pten. Mechanistically, Sox4 ablation reduced activation of AKT and β-catenin, leading to an attenuated invasive phenotype. Furthermore, SOX4 expression was induced by Pten loss as a result of the activation of PI3K–AKT–mTOR signaling, suggesting a positive feedback loop between SOX4 and PI3K–AKT–mTOR activity. Collectively, our findings establish that SOX4 is a critical component of the PTEN/PI3K/AKT pathway in prostate cancer, with potential implications for combination-targeted therapies against both primary and advanced prostate cancers. Cancer Res; 76(5); 1112–21. ©2015 AACR.
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Sirolimus
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An increasing amount of evidence has shown that tumor suppressors can become oncogenes, or vice versa, but the mechanism behind this is unclear. Recent findings have suggested that phosphatase and tensin homolog (PTEN) is one of the powerful switches for the conversion between tumor suppressors and oncogenes. PTEN regulates a number of cellular processes, including cell death and proliferation, through the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Furthermore, a number of studies have suggested that PTEN deletions may alter various functions of certain tumor suppressor and oncogenic proteins. The aim of the present review was to analyze specific cases driven by PTEN loss/AKT activation, including aberrant signaling pathways and novel drug targets for clinical application in personalized medicine. The findings illustrate how PTEN loss and/or AKT activation switches MDM2-dependent p53 downregulation, and induces conversion between oncogene and tumor suppressor in enhancer of zeste homolog 2, BTB domain-containing 7A, alternative reading frame 2, p27 and breast cancer 1, early onset, through multiple mechanisms. This review highlights the genetic basis of complex drug targets and provides insights into the rationale of precision cancer therapy.
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Abstract : Breast cancer is the most common malignancy in women. The recently identified tumor suppressor gene PTEN has turned out to be a promising candidate for mammary tumorigenesis. Mice heterozygous for Pten develops mammary tumors starting from 6 weeks. The goal of this project is to determine the role of AKT, a major downstream target of PI3K pathway, in PTEN mediated mammary tumor development. To study the function of AKT in breast cancer development, we have deleted AKT gene and are studying its role both in vivo and in vitro. In cell culture, we demonstrated that AKT is not only responsible for the survival phenotype but also important for the cell proliferation phenotype of Pten null ES cells. In vivo analysis demonstrated that deletion of Akt on top of Pten resulted in both decreased tumor occurence and shorter tumor onset as well as increased lifespan.
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Tumor suppressors function in a coordinated regulatory network, and their inactivation is a key step in carcinogenesis. The tumor suppressor Par-4 is a novel integral player in the PTEN network. Thus, Par-4 is absent in a high percentage of human prostate carcinomas, and its loss is concomitantly associated with PTEN loss. Genetic ablation of Par-4 induces fully invasive prostate carcinomas in PTEN-heterozygous mice. In contrast, Par-4 deficiency alone, like PTEN heterozygosis, results in lesions that are unable to progress beyond the benign neoplastic stage known as PIN. At this PIN transition, the mutual induction of Par-4 and PTEN is an additional regulatory step in preventing cancer progression. Par-4 deficiency cooperates with PTEN haploinsufficiency in prostate cancer initiation and progression and their simultaneous inactivation, in addition to enhancing Akt activation, sets in motion a unique mechanism involving the synergistic activation of NF-κB. These results suggest that the concurrent interruption of complementary signaling pathways targeting PI3K/Akt and NF-κB activation could provide new and effective strategies for cancer therapy.
Haploinsufficiency
Tumor progression
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Abnormal microRNA (miR) expressions were implicated in prostate cancer progression. We identified a novel miR-495, which was downregulated in prostate cancer, but not normal prostate cell lines. MiR-495 directly targeted the 3′-UTR of Akt and mTOR mRNAs. Expression of miR-495 in prostate cancer cells significantly downregulated Akt and mTOR, which further inhibited cancer cell proliferation, migration, and invasion in vitro. Function of miR-495 in vivo was examined in mouse xenograft model and was found to significantly inhibit the growth of tumors, mediated by repressing Akt and mTOR. Our report supported miR-495 as a novel tumor suppressor microRNA in prostate cancer.
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The conversion of benign tumour to malignancy depends on a complex combination of the genetic mutation milieu and the sentinel systems that resist carcinogenesis. In transgenic mouse skin carcinogenesis driven by rasHa/fos activation [HK1.ras/fos] and RU486-induced PTEN loss, we previously demonstrated that [HK1.ras/fos-Δ5PTENflx malignant conversion was delayed and progression limited to well-differentiated SSC histotypes [wdSCC]. This delay was associated with elevated p53/p21 expression until p53 was lost in late-stage papillomas, whereas p21 persisted and limit early-stage progression to wdSCCs. Given the regulation of AKT, and its target mTOR, by PTEN, we now determined their stage-specific expression profiles and found that, despite PTEN loss, expression of activated AKT [p-AKT] was low/absent in [HK1.ras/fos-Δ5PTENflx hyperplasia, papillomas and sporadic in wdSCCs. With time, p-AKT expression increased in p53 –negative wdSCCs and concomitant with this rise, punctate, nuclear p21 expression in basal layers became increasingly cytoplasmic, giving a peri-nuclear staining pattern. Hence early progression may involve an AKT-mediated exclusion of p21 from the nucleus, and once p-AKT expression became uniform in overt SCCs, p21 expression was undetectable. In being a major target of AKT activation, a similar profile was envisaged for m-TOR. However unlike p-AKT, p-mTOR was strongly expressed in [HK1.ras/fos-Δ5PTENflx hyperplasia, alongside strong p53/p21, persisted in p21 positive/p53 negative wdSCCs, but then faded on progression to aggressive SCCs, despite uniform p-AKT expression. These data suggest once p53 was lost, elevated [AKT-independent] p-mTOR expression cooperated with ras/fos in a converting role, whilst AKT expression exerts major effect in later progression via inhibition of p21.
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