Prostate cancer is a heterogeneous disease that remains dormant for long periods or acts aggressively with poor clinical outcomes. Identifying aggressive prostate tumor behavior using current ...glandular-focused histopathological criteria is challenging. Recent evidence has implicated the stroma in modulating prostate tumor behavior and in predicting post-surgical outcomes. However, the emergence of stromal signatures has been limited, due in part to the lack of adoption of imaging modalities for stromal-specific profiling. Herein, label-free multiphoton microscopy (MPM), with its ability to image tissue with stromal-specific contrast, is used to identify prostate stromal features associated with aggressive tumor behavior and clinical outcome. MPM was performed on unstained prostatectomy specimens from 59 patients and on biopsy specimens from 17 patients with known post-surgery recurrence status. MPM-identified collagen content, organization, and morphological tumor signatures were extracted for each patient and screened for association with recurrent disease. Compared to tumors from patients whose disease did not recur, tumors from patients with recurrent disease exhibited higher MPM-identified collagen amount and collagen fiber intensity signal and width. Our study shows an association between MPM-identified stromal collagen features of prostate tumors and post-surgical disease recurrence, suggesting their potential for prostate cancer risk assessment.
Using RNA sequencing of triple-negative breast cancer (TNBC), non-TBNC and HER2-positive breast cancer sub-types, here we report novel expressed variants, allelic prevalence and abundance, and ...coexpression with other variation, and splicing signatures. To reveal the most prevalent variant alleles, we overlaid our findings with cancer- and population-based datasets and validated a subset of novel variants of cancer-related genes: ESRP2, GBP1, TPP1, MAD2L1BP, GLUD2 and SLC30A8. As a proof-of-principle, we demonstrated that a rare substitution in the splicing coordinator ESRP2 (R353Q) impairs its ability to bind to its substrate FGFR2 pre-mRNA. In addition, we describe novel SNPs and INDELs in cancer relevant genes with no prior reported association of point mutations with cancer, such as MTAP and MAGED1. For the first time, this study illustrates the power of RNA-sequencing in revealing the variation landscape of breast transcriptome and exemplifies analytical strategies to search regulatory interactions among cancer relevant molecules.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has resulted in a global health emergency, the like of which has never been seen before. Prostate cancer (PCa) services ...across the globe have been on hold due to changing medical and surgical priorities. There is also epidemiological evidence that PCa patients have increased incidence and mortality from SARS-CoV-2 infection due to gender differences, age, and higher propensity for risk factors (eg, respiratory disease, obesity, hypertension, and smoking status).
To contribute to the emerging body of knowledge on the risks of SARS-CoV-2 infection to PCa patients and, in the face of PCa treatment delays, provide evidence-based recommendations for ongoing management of specific PCa patient groups.
A literature search was performed using all sources (MEDLINE, EMBASE, ScienceDirect, Cochrane Libraries, and Web of Science) as well as the media to harness emerging data on the SARS-CoV-2 pandemic and its influence on PCa. Eligibility criteria were originality of data and relevance to PCa management. The authors note that during these unprecedented times, retrospective data are constantly being updated from multiple sources globally.
A total of 72 articles and data sources were found initially. Owing to repetition, lack of originality, or nonrelevance, six articles were rejected, leaving 23 retrospective studies, seven basic science research articles, 15 societal and journal guidelines, and 21 epidemiological data sources, from countries at different stages of SARS-CoV-2 pandemic. These were analyzed qualitatively to produce evidence-based guidelines for the management of PCa patients at different stages of the patient journey, with strategies to reduce the risk of viral spread.
PCa patients may have an increased risk of SARS-CoV-2 infection as well as morbidity and mortality if infected. Once appropriately triaged, and to reduce viral spread, PCa patients can have surveillance by telemedicine, and institute lifestyle changes and social quarantining measures. If risk stratification suggests that treatment should be planned, androgen deprivation therapy can be started, or potentially surgery or radiation therapy is possible on a case-by-case basis.
Prostate cancer patients can be followed up remotely until the severe acute respiratory syndrome coronavirus 2 pandemic resolves, but higher-risk cases may have treatment expedited to limit any negative impact on prostate cancer outcomes.
Prostate cancer (PCa) patients may have an increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and mortality. Most can be followed up remotely until the pandemic resolves, but, once appropriately triaged, higher-risk cases can have treatment expedited to limit any negative impact on PCa outcomes.
It is increasingly accepted that steroidal receptor co-regulators may also function in the cytoplasmic compartment. Proline-, glutamic acid-, and leucine-rich protein-1 (PELP1) is a novel coregulator ...that plays a role in both the genomic and extranuclear actions of estrogen receptors (ER) in hormonally responsive tissues. In this study using breast tumor arrays, we found that PELP1 was localized only in the cytoplasm in 58% of the PELP1-positive breast tumors. To help explain the significance of the cytoplasmic localization of PELP1 in human breast tumors, we created a mutant protein that was expressed only in the cytoplasm (PELP1-cyto) and then generated a model system wherein MCF-7 breast cancer cells were engineered to specifically express this mutant. We found that PELP1-cyto cells were hypersensitive to estrogen but resistant to tamoxifen. PELP1-cyto cells, but not parental MCF-7 cells, formed xenograft tumors in nude mice. In addition, PELP1-cyto cells exhibited increased association of PELP1 with Src, enhanced mitogen-activated protein kinase (MAPK) activation, and constitutive activation of AKT. The altered localization of PELP1 was sufficient to trigger the interaction of PELP1 with the p85 subunit of phosphatidylinositol-3-kinase (PI3K), leading to PI3K activation. In addition, PELP1 interacted with epidermal growth factor receptors and participated in growth factor-mediated ER transactivation functions. Our results suggest that the altered localization of PELP1 modulates sensitivity to antiestrogens, potentiates tumorigenicity, presumably via the stimulation of extranuclear estrogen responses, such as the activation of MAPK and AKT, and also enhance cross-regulation of ER transactivation activity by growth factors.
Although both metastatic tumor antigen 1 (MTA1), a master chromatin modifier, and transglutaminase 2 (TG2), a multifunctional enzyme, are known to be activated during inflammation, it remains unknown ...whether these molecules regulate inflammatory response in a coordinated manner. Here we investigated the role of MTA1 in the regulation of TG2 expression in bacterial lipopolysaccharide (LPS)-stimulated mammalian cells. While studying the impact of MTA1 status on global gene expression, we unexpectedly discovered that MTA1 depletion impairs the basal as well as the LPS-induced expression of TG2 in multiple experimental systems. We found that TG2 is a chromatin target of MTA1 and of NF-κB signaling in LPS-stimulated cells. In addition, LPS-mediated stimulation of TG2 expression is accompanied by the enhanced recruitment of MTA1, p65RelA, and RNA polymerase II to the NF-κB consensus sites in the TG2 promoter. Interestingly, both the recruitment of p65 and TG2 expression are effectively blocked by a pharmacological inhibitor of the NF-κB pathway. These findings reveal an obligatory coregulatory role of MTA1 in the regulation of TG2 expression and of the MTA1-TG2 pathway, at least in part, in LPS modulation of the NF-κB signaling in stimulated macrophages.
The nonpolymorphic major histocompatibility complex E (MHC-E) molecule is up-regulated on many cancer cells, thus contributing to immune evasion by engaging inhibitory NKG2A/CD94 receptors on NK ...cells and tumor-infiltrating T cells. To investigate whether MHC-E expression by cancer cells can be targeted for MHC-E-restricted T cell control, we immunized rhesus macaques (RM) with rhesus cytomegalovirus (RhCMV) vectors genetically programmed to elicit MHC-E-restricted CD8
T cells and to express established tumor-associated antigens (TAAs) including prostatic acidic phosphatase (PAP), Wilms tumor-1 protein, or Mesothelin. T cell responses to all three tumor antigens were comparable to viral antigen-specific responses with respect to frequency, duration, phenotype, epitope density, and MHC restriction. Thus, CMV-vectored cancer vaccines can bypass central tolerance by eliciting T cells to noncanonical epitopes. We further demonstrate that PAP-specific, MHC-E-restricted CD8
T cells from RhCMV/PAP-immunized RM respond to PAP-expressing HLA-E
prostate cancer cells, suggesting that the HLA-E/NKG2A immune checkpoint can be exploited for CD8
T cell-based immunotherapies.
The estrogen receptor plays an important role in breast cancer progression. Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1), also called modulator of nongenomic activity of estrogen ...receptor (MNAR), a novel coactivator of estrogen receptor, modulates estrogen receptor transactivation functions. The mechanisms by which PELP1 modulates estrogen receptor genomic functions is not known. Here, using biochemical and scanning confocal microscopic analysis, we have demonstrated nuclear localization and functional implications of PELP1. Subnuclear fractionation showed PELP1 association with chromatin and nuclear matrix fractions. Ligand stimulation promoted recruitment of PELP1 to 17beta-estradiol responsive promoters, its colocalization with acetylated H3, and increased PELP1-associated histone acetyltransferase enzymatic activity. Far Western analysis revealed that PELP1 interacts with histone 1 and 3, with more preference toward histone 1. Using deletion analysis, we have identified the PELP1 COOH-terminal region as the histone 1 binding site. The PELP1 mutant lacking histone 1-binding domain acts as a dominant-negative and blocks estrogen receptor alpha-mediated transcription. Chromatin immunoprecipitation analysis showed a cyclic association and dissociation of PELP1 with the promoter, with recruitment of histone 1 and PELP1 occurring in opposite phases. PELP1 overexpression increased the micrococcal nuclease sensitivity of estrogen response element-containing nucleosomes. Our results provide novel insights about the transcription regulation of PELP1 and suggest that PELP1 participates in chromatin remodeling activity via displacement of histone 1 in cancer cells.
Proline-, glutamic acid-, and leucine-rich protein-1 (PELP1) is a novel estrogen receptor coactivator that plays an important role in the genomic and nongenomic actions of estrogen receptor by ...interacting with histones and src-mitogen-activated protein kinase pathway, respectively. A great deal of information has emerged in recent years about the possible role of PELP1 in estrogen receptor signaling. However, the participation and significance of PELP1 in other cellular signaling pathways remains unknown. Using a yeast two-hybrid screen, we identified PELP1 as a novel interacting protein of signal transducers and activators of transcription 3 (STAT3) and found evidence of physiologic interaction between PELP1 and STAT3. We also found that these interactions played a mechanistic role in the positive regulation of STAT3 transcription from synthetic promoters and endogenous target genes such as cyclin D1, c-myc, and c-fos. Overexpression of PELP1 enhanced phosphorylation of STAT3 at Ser727 in a src-mitogen-activated protein kinase-sensitive manner and, conversely, down-regulation of PELP1 compromised growth factor-mediated induction of STAT3 target genes. We also discovered that PELP1 interacts with STAT3 in the nuclear compartment and down-regulation of PELP1 interfered with the recruitment of STAT3 to its target gene promoters. In summary, our results highlight a novel role for PELP1 in growth factor signaling and indicate that PELP1-mediated genomic and nongenomic functions play a role in the growth factor-mediated STAT3 transactivation functions. Such regulatory interactions of PELP1 may have important functional implications in the cross-talk of estrogen receptor and growth factor signaling.
Sulforaphane (SFN) and its N-acetyl-L-cysteine (NAC) conjugate are effective inhibitors of tumorigenesis in animal models. These compounds induce the expression of the antioxidant response element ...(ARE)-related genes and cause apoptosis. We studied the role of reduced glutathione (GSH) in the activations of ARE-mediated gene expression, apoptosis, and the activation of c-Jun NH(2)-terminal kinase (JNK) in HepG2-C8 cells. The cellular level of GSH decreased transiently when cells were exposed to SFN and then increased from 4 h, reaching 2.2-fold over control at 24 h. In contrast, SFN-NAC did not change the GSH level substantially during the time of incubation. ARE expression was increased in a dose-dependent manner up to 35 micro M SFN and 75 micro M SFN-NAC, respectively. The induction of ARE by SFN was 8.6-fold higher than that by SFN-NAC. Pretreatment with L-buthionine sulfoximine increased SFN-induced ARE expression significantly. The decrease in ARE expression at higher concentrations of SFN and SFN-NAC was correlated with accelerated apoptotic cell death, with a dose-dependent activation of caspase 3 activity by SFN. On addition of extracellular GSH within 6 h of treatment with SFN, the effect on ARE expression was blocked almost completely. SFN was able to activate JNK1/2, and that activation was blocked by treatment with exogenous GSH. Taken together, these results suggest that the biological effects of SFN and SFN-NAC on the induction of ARE-related gene expression and apoptosis could be different from each other; however, the different effects on ARE-related gene expression and apoptosis elicited by SFN can be blocked by the addition of GSH.
Based on the recently established role for the master coregulator MTA1 and MTA1‐containing nuclear remodeling complexes in oncogenesis and inflammation, we explored the links between parasitism by ...the carcinogenic liver fluke Opisthorchis viverrini and this coregulator using both an Mta1−/− mouse model of infection and a tissue microarray of liver fluke–induced human cholangiocarcinomas (CCAs). Intense foci of inflammation and periductal fibrosis in the liver and kidneys of wild‐type Mta1+/+ mice were evident at 23 days postinfection with O. viverrini. In contrast, little inflammatory response was observed in the same organs of infected Mta1−/− mice. Livers of infected Mta1+/+ mice revealed strong up‐regulation of fibrosis‐associated markers such as cytokeratins 18 and 19 and annexin 2, as determined both by immunostaining and by reverse‐transcription polymerase chain reaction compared with infected Mta1−/− mice. CD4 expression was up‐regulated by infection in the livers of both experimental groups; however, its levels were several‐fold higher in the Mta1+/+ mice than in infected Mta1−/− mice. Mta1−/− infected mice also exhibited significantly higher systemic and hepatic levels of host cytokines such as interleukin (IL)‐12p70, IL‐10, and interferon‐γ compared with the levels of these cytokines in the Mta1+/+ mice, suggesting an essential role of MTA1 in the cross‐regulation of the Th1 and Th2 responses, presumably due to chromatin remodeling of the target chromatin genes. Immunohistochemical analysis of ≈300 liver tissue cores from confirmed cases of O. viverrini–induced CCA showed that MTA1 expression was elevated in >80% of the specimens. Conclusion: These findings suggest that MTA1 status plays an important role in conferring an optimal cytokine response in mice following infection with O. viverrini and is a major player in parasite‐induced CCA in humans. (HEPATOLOGY 2011;)
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