scholarly journals Regulatory mechanisms of phosphatase of regenerating liver (PRL)-3

2016 ◽  
Vol 44 (5) ◽  
pp. 1305-1312 ◽  
Author(s):  
Teresa Rubio ◽  
Maja Köhn
Keyword(s):  
Drug Development ◽  
Posttranslational Modifications ◽  
Human Cancer ◽  
Regulatory Mechanisms ◽  
Therapeutic Drug ◽  
Regenerating Liver ◽  
Cancer Types ◽  
Tumor Metastases ◽  
Phosphatase Of Regenerating Liver ◽  
Incomplete Picture

The phosphatase of regenerating liver (PRL)-3 is overexpressed in many human cancer types and tumor metastases when compared with healthy tissues. Different pathways and mechanisms have been suggested to modulate PRL-3 expression levels and activity, giving some valuable insights but still leaving an incomplete picture. Investigating these mechanisms could provide new targets for therapeutic drug development. Here, we present an updated overview and summarize recent findings concerning the different PRL-3 expression regulatory mechanisms and posttranslational modifications suggested to modulate the activity, localization, or stability of this phosphatase.

scholarly journals Pan-cancer analysis of RNA binding proteins (RBPs) reveals the involvement of the core pre-mRNA splicing and translation machinery in tumorigenesis

2018 ◽  
Author(s):  
Bin Zhang ◽  
Kamesh R. Babu ◽  
Chun You Lim ◽  
Zhi Hao Kwok ◽  
Jia Li ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Copy Number ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Human Cancer ◽  
Mrna Splicing ◽  
Regulatory Mechanisms ◽  
Translation Machinery ◽  
The Core ◽  
Cancer Types

AbstractRNA binding proteins (RBPs) are key regulators of posttranscriptional processes such as RNA maturation, transport, localization, turnover and translation. Despite their dysregulation in various diseases including cancer, the landscape of RBP expression and regulatory mechanisms in human cancer has not been well characterized. Here, we analyzed mRNA expression of 1487 RBPs in ~6700 clinical samples across 16 human cancer types and found that there were significantly more upregulated RBPs than downregulated ones in tumors when compared to their adjacent normal tissues. Across almost all of the 16 cancer types, 109 RBPs were consistently upregulated (cuRBPs) while only 41 RBPs were consistently downregulated (cdRBPs). Integrating expression with the copy number and DNA methylation data, we found that the overexpression of cuRBPs is largely associated with the amplification of copy number, whereas the downregulation of cdRBPs may be a result of epigenetic silencing mediated by DNA methylation. Furthermore, our results indicated that cuRBPs could work together to promote cancer progression potentially through the involvement of splicing and translation machinery, while cdRBPs might function independently to suppress tumorigenesis. Additionally, we focused on colon cancer and identified several novel potential oncogenic RBPs, such as PABPC1L which might promote cancer development via regulating the core splicing machinery. In summary, we showed distinct expression landscapes, regulatory mechanisms and characteristics of cuRBPs and cdRBPs and implicated several novel RBPs in cancer pathogenesis. Moreover, our results suggest that the involvement of the core pre-mRNA splicing and translation machinery could be critical in tumorigenesis.

scholarly journals Prioritisation of oncology therapeutic targets using CRISPR-Cas9 screening

2018 ◽  
Author(s):  
Fiona M Behan ◽  
Francesco Iorio ◽  
Emanuel Gonçalves ◽  
Gabriele Picco ◽  
Charlotte M Beaver ◽  
...  
Keyword(s):  
Drug Development ◽  
Werner Syndrome ◽  
Human Cancer ◽  
Target Identification ◽  
Recq Helicase ◽  
Human Cancer Cell Lines ◽  
Fitness Effects ◽  
Candidate Target ◽  
Cancer Types ◽  
Genome Scale

SummaryFunctional genomics approaches can overcome current limitations that hamper oncology drug development such as lack of robust target identification and clinical efficacy. Here we performed genome-scale CRISPR-Cas9 screens in 204 human cancer cell lines from 12 cancer-types and developed a data-driven framework to prioritise cancer therapeutic candidates. We integrated gene cell fitness effects with genomic biomarkers and target tractability for drug development to systematically prioritise new oncology targets in defined tissues and genotypes. Furthermore, we took one of our most promising dependencies, Werner syndrome RecQ helicase, and verified it as a candidate target for tumours with microsatellite instability. Our analysis provides a comprehensive resource of cancer dependencies, a framework to prioritise oncology targets, and nominates specific new candidates. The principles described in this study can transform the initial stages of the drug development process contributing to a new, diverse and more effective portfolio of oncology targets.

Plasminogen Receptors in Human Malignancies: Effects on Prognosis and Feasibility as Targets for Drug Development

2020 ◽  
Vol 21 (7) ◽  
pp. 647-656
Author(s):  
Steven L. Gonias ◽  
Carlotta Zampieri
Keyword(s):  
Growth Factors ◽  
Drug Development ◽  
Plasminogen Activator ◽  
Human Cancer ◽  
Annexin A2 ◽  
The Cancer Genome Atlas ◽  
Tissue Type ◽  
Cell Surfaces ◽  
Ecm Proteins ◽  
Type Plasminogen Activator

The major proteases that constitute the fibrinolysis system are tightly regulated. Protease inhibitors target plasmin, the protease responsible for fibrin degradation, and the proteases that convert plasminogen into plasmin, including tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). A second mechanism by which fibrinolysis is regulated involves exosite interactions, which localize plasminogen and its activators to fibrin, extracellular matrix (ECM) proteins, and cell surfaces. Once plasmin is generated in association with cell surfaces, it may cleave transmembrane proteins, activate growth factors, release growth factors from ECM proteins, remodel ECM, activate metalloproteases, and trigger cell-signaling by cleaving receptors in the Proteaseactivated Receptor (PAR) family. These processes are all implicated in cancer. It is thus not surprising that a family of structurally diverse but functionally similar cell-surface proteins, called Plasminogen Receptors (PlgRs), which increase the catalytic efficiency of plasminogen activation, have received attention for their possible function in cancer and as targets for anticancer drug development. In this review, we consider four previously described PlgRs, including: α-enolase, annexin-A2, Plg-RKT, and cytokeratin-8, in human cancer. To compare the PlgRs, we mined transcriptome profiling data from The Cancer Genome Atlas (TCGA) and searched for correlations between PlgR expression and patient survival. In glioma, the expression of specific PlgRs correlates with tumor grade. In a number of malignancies, including glioblastoma and liver cancer, increased expression of α-enolase or annexin-A2 is associated with an unfavorable prognosis. Whether these correlations reflect the function of PlgRs as receptors for plasminogen or other activities is discussed.

scholarly journals Histone deacetylase (HDAC) 9: versatile biological functions and emerging roles in human cancer

2021 ◽  
Author(s):  
Chun Yang ◽  
Stéphane Croteau ◽  
Pierre Hardy
Keyword(s):  
Histone Deacetylase ◽  
Posttranslational Modifications ◽  
Histone Deacetylases ◽  
Muscle Development ◽  
Target Genes ◽  
Human Cancer ◽  
Expression Patterns ◽  
Aberrant Expression ◽  
Physiological Processes ◽  
Cancer Pathogenesis

Abstract Background HDAC9 (histone deacetylase 9) belongs to the class IIa family of histone deacetylases. This enzyme can shuttle freely between the nucleus and cytoplasm and promotes tissue-specific transcriptional regulation by interacting with histone and non-histone substrates. HDAC9 plays an essential role in diverse physiological processes including cardiac muscle development, bone formation, adipocyte differentiation and innate immunity. HDAC9 inhibition or activation is therefore a promising avenue for therapeutic intervention in several diseases. HDAC9 overexpression is also common in cancer cells, where HDAC9 alters the expression and activity of numerous relevant proteins involved in carcinogenesis. Conclusions This review summarizes the most recent discoveries regarding HDAC9 as a crucial regulator of specific physiological systems and, more importantly, highlights the diverse spectrum of HDAC9-mediated posttranslational modifications and their contributions to cancer pathogenesis. HDAC9 is a potential novel therapeutic target, and the restoration of aberrant expression patterns observed among HDAC9 target genes and their related signaling pathways may provide opportunities to the design of novel anticancer therapeutic strategies.

scholarly journals The Impact of COVID‐19 on Pregnancy and Therapeutic Drug Development

2021 ◽  
Author(s):  
Allyah Abbas‐Hanif ◽  
Homira Rezai ◽  
S. Faraz Ahmed ◽  
Asif Ahmed
Keyword(s):  
Drug Development ◽  
Therapeutic Drug ◽  
The Impact

scholarly journals Cellular Fitness Phenotypes of Cancer Target Genes from Oncobiology to Cancer Therapeutics

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 433
Author(s):  
Bijesh George ◽  
P. Mukundan Pillai ◽  
Aswathy Mary Paul ◽  
Revikumar Amjesh ◽  
Kim Leitzel ◽  
...  
Keyword(s):  
Drug Targets ◽  
Target Genes ◽  
Human Cancer ◽  
Cancer Therapeutics ◽  
Survival Duration ◽  
Cancer Drug ◽  
Targeted Therapeutics ◽  
Cellular Targets ◽  
Human Cancer Cells ◽  
Cancer Types

To define the growing significance of cellular targets and/or effectors of cancer drugs, we examined the fitness dependency of cellular targets and effectors of cancer drug targets across human cancer cells from 19 cancer types. We observed that the deletion of 35 out of 47 cellular effectors and/or targets of oncology drugs did not result in the expected loss of cell fitness in appropriate cancer types for which drugs targeting or utilizing these molecules for their actions were approved. Additionally, our analysis recognized 43 cellular molecules as fitness genes in several cancer types in which these drugs were not approved, and thus, providing clues for repurposing certain approved oncology drugs in such cancer types. For example, we found a widespread upregulation and fitness dependency of several components of the mevalonate and purine biosynthesis pathways (currently targeted by bisphosphonates, statins, and pemetrexed in certain cancers) and an association between the overexpression of these molecules and reduction in the overall survival duration of patients with breast and other hard-to-treat cancers, for which such drugs are not approved. In brief, the present analysis raised cautions about off-target and undesirable effects of certain oncology drugs in a subset of cancers where the intended cellular effectors of drug might not be good fitness genes and that this study offers a potential rationale for repurposing certain approved oncology drugs for targeted therapeutics in additional cancer types.

scholarly journals Transporter associated with antigen processing 1 (TAP1) expression and prognostic analysis in breast, lung, liver, and ovarian cancer

2021 ◽  
Author(s):  
Anika Tabassum ◽  
Md. Nazmus Samdani ◽  
Tarak Chandra Dhali ◽  
Rahat Alam ◽  
Foysal Ahammad ◽  
...  
Keyword(s):  
Expression Pattern ◽  
Cancer Progression ◽  
Antigen Processing ◽  
Human Cancer ◽  
Analytical Data ◽  
Significant Negative Correlation ◽  
Cancer Tissue ◽  
Human Cancer Cell Lines ◽  
Prognostic Analysis ◽  
Cancer Types

Abstract Transporter associated with antigen processing 1 (TAP1) is a transporter protein that represent tumor antigen in the MHC I or HLA complex. Any defect in the TAP1 gene resulting in inadequate tumor tracking. TAP1 influences multidrug resistance (MDR) in human cancer cell lines and hinders the treatment during chemotherapeutic. The association of TAP1 in cancer progression remains mostly unknown and further study of the gene in relation with cancer need to conduct. Thus, the study has designed to analyze the association between the TAP1 with cancer by computationally. The expression pattern of the gene has determined by using ONCOMINE, GENT2, and GEPIA2 online platforms. The protein level of TAP1 was examined by the help of Human Protein Atlas. Samples with different clinical outcomes were investigated to evaluate the expression and promoter methylation in cancer vs. normal tissues by using UALCAN server. The copy number alteration, mutation frequency, and expression level of the gene in different cancer were analyzed by using cBioPortal server. The PrognoScan and KM plotter platforms were used to perform the survival analysis and represented graphically. Additionally, pathway and gene ontology (GO) features correlated to the TAP1 gene were analyzed and presented by bar charts. After arranging the data in a single panel like correlating expression to prognosis, mutational and alterations characteristic, and pathways analysis, we observed some interesting insights that emphasized the importance of the gene in cancer progression. The study found the relationship between the TAP1 expression pattern and prognosis in different cancer tissues and shows how TAP1 affects the clinical characteristics. The analytical data presented in the study is vital to learn about the effect of TAP1 in tumor tissue, where previously studies showing contradicting expression of TAP1 in cancer tissue. The analyzed data can also be utilized further to evade the threats against chemotherapy. Overall, the study provided a new aspect to consider the role of TAP1 gene in cancer progression and survival status. Key messages • This study demonstrated, for the first time, a correlation between the TAP1 gene and tumor progression. • An upregulation of TAP1 mRNA was demonstrated in various cancer types. • This study reported a significant negative correlation for TAP1 gene expression and the survival rate in different cancer types.

scholarly journals Lights and Shadows in Immuno-Oncology Drug Development

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 691
Author(s):  
Milana Bergamino Sirvén ◽  
Sonia Pernas ◽  
Maggie C. U. Cheang
Keyword(s):  
Drug Development ◽  
Checkpoint Inhibitors ◽  
Late Phase ◽  
New Drugs ◽  
Successful Outcome ◽  
Different Types ◽  
Cancer Types ◽  
Clinical Trial Designs ◽  
Oncology Drug Development ◽  
Critical Aspects

The rapidly evolving landscape of immuno-oncology (IO) is redefining the treatment of a number of cancer types. IO treatments are becoming increasingly complex, with different types of drugs emerging beyond checkpoint inhibitors. However, many of the new drugs either do not progress from phase I-II clinical trials or even fail in late-phase trials. We have identified at least five areas in the development of promising IO treatments that should be redefined for more efficient designs and accelerated approvals. Here we review those critical aspects of IO drug development that could be optimized for more successful outcome rates in all cancer types. It is important to focus our efforts on the mechanisms of action, types of response and adverse events of these novel agents. The use of appropriate clinical trial designs with robust biomarkers of response and surrogate endpoints will undoubtedly facilitate the development and subsequent approval of these drugs. Further research is also needed to establish biomarker-driven strategies to select which patients may benefit from immunotherapy and identify potential mechanisms of resistance.

Application Of LIF Technique In The Diagnosis Of Some Human Cancer Types

2009 ◽  
Author(s):  
A. El-Hussein ◽  
H. Ismail ◽  
A. K. Kasem ◽  
M. A. Harith ◽  
Mohamed Abdel Harith
Keyword(s):  
Human Cancer ◽  
Cancer Types
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