scholarly journals Dynamic rewiring of biological activity across genotype and lineage revealed by context-dependent functional interactions

2021 ◽  
Author(s):  
Eiru Kim ◽  
Veronica Gheorghe ◽  
Traver Hart
Keyword(s):  
Cell Lines ◽  
Drug Targeting ◽  
Strong Interactions ◽  
Specific Gene ◽  
Tumor Type ◽  
Functional Interactions ◽  
Oncogenic Mutation ◽  
Context Dependent ◽  
Lineage Specific Gene

Coessentiality networks derived from CRISPR screens in cell lines provide a powerful framework for identifying functional modules in the cell and for inferring the role of uncharacterized genes. However, these networks integrate signal across all underlying data, and can mask strong interactions that occur in only a subset of the cell lines analyzed. Here we decipher dynamic functional interactions by identifying significant cellular contexts, primarily by oncogenic mutation, lineage, and tumor type, and discovering coessentiality relationships that depend on these contexts. We recapitulate well-known gene-context interactions such as oncogene-mutation, paralog buffering, and tissue-specific essential genes, show how mutation rewires known signal transduction pathways, including RAS/RAF and IGF1R-PIK3CA, and illustrate the implications for drug targeting. We further demonstrate how context-dependent functional interactions can elucidate lineage-specific gene function, as illustrated by the maturation of proreceptors IGF1R and MET by proteases FURIN and CPD. This approach advances our understanding of context-dependent interactions and how they can be gleaned from these data.

scholarly journals STAT3 and STAT5 Activation in Solid Cancers

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1428 ◽  
Author(s):  
Sebastian Igelmann ◽  
Heidi Neubauer ◽  
Gerardo Ferbeyre
Keyword(s):  
Tumor Suppressor ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Critical Role ◽  
Control Cell ◽  
Cytokine Signaling ◽  
Specific Gene ◽  
Mitochondrial Functions ◽  
Context Dependent

The Signal Transducer and Activator of Transcription (STAT)3 and 5 proteins are activated by many cytokine receptors to regulate specific gene expression and mitochondrial functions. Their role in cancer is largely context-dependent as they can both act as oncogenes and tumor suppressors. We review here the role of STAT3/5 activation in solid cancers and summarize their association with survival in cancer patients. The molecular mechanisms that underpin the oncogenic activity of STAT3/5 signaling include the regulation of genes that control cell cycle and cell death. However, recent advances also highlight the critical role of STAT3/5 target genes mediating inflammation and stemness. In addition, STAT3 mitochondrial functions are required for transformation. On the other hand, several tumor suppressor pathways act on or are activated by STAT3/5 signaling, including tyrosine phosphatases, the sumo ligase Protein Inhibitor of Activated STAT3 (PIAS3), the E3 ubiquitin ligase TATA Element Modulatory Factor/Androgen Receptor-Coactivator of 160 kDa (TMF/ARA160), the miRNAs miR-124 and miR-1181, the Protein of alternative reading frame 19 (p19ARF)/p53 pathway and the Suppressor of Cytokine Signaling 1 and 3 (SOCS1/3) proteins. Cancer mutations and epigenetic alterations may alter the balance between pro-oncogenic and tumor suppressor activities associated with STAT3/5 signaling, explaining their context-dependent association with tumor progression both in human cancers and animal models.

scholarly journals Arachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Mario Cioce ◽  
Claudia Canino ◽  
Harvey Pass ◽  
Giovanni Blandino ◽  
Sabrina Strano ◽  
...  
Keyword(s):  
Gene Expression ◽  
Arachidonic Acid ◽  
Cell Lines ◽  
Adaptive Response ◽  
Response To Therapy ◽  
Specific Gene ◽  
Induced Stress ◽  
Cell Subpopulations ◽  
Transformed Cell Lines

Abstract Background High resistance to therapy and poor prognosis characterizes malignant pleural mesothelioma (MPM). In fact, the current lines of treatment, based on platinum and pemetrexed, have limited impact on the survival of MPM patients. Adaptive response to therapy-induced stress involves complex rearrangements of the MPM secretome, mediated by the acquisition of a senescence-associated-secretory-phenotype (SASP). This fuels the emergence of chemoresistant cell subpopulations, with specific gene expression traits and protumorigenic features. The SASP-driven rearrangement of MPM secretome takes days to weeks to occur. Thus, we have searched for early mediators of such adaptive process and focused on metabolites differentially released in mesothelioma vs mesothelial cell culture media, after treatment with pemetrexed. Methods Mass spectrometry-based (LC/MS and GC/MS) identification of extracellular metabolites and unbiased statistical analysis were performed on the spent media of mesothelial and mesothelioma cell lines, at steady state and after a pulse with pharmacologically relevant doses of the drug. ELISA based evaluation of arachidonic acid (AA) levels and enzyme inhibition assays were used to explore the role of cPLA2 in AA release and that of LOX/COX-mediated processing of AA. QRT-PCR, flow cytometry analysis of ALDH expressing cells and 3D spheroid growth assays were employed to assess the role of AA at mediating chemoresistance features of MPM. ELISA based detection of p65 and IkBalpha were used to interrogate the NFkB pathway activation in AA-treated cells. Results We first validated what is known or expected from the mechanism of action of the antifolate. Further, we found increased levels of PUFAs and, more specifically, arachidonic acid (AA), in the transformed cell lines treated with pemetrexed. We showed that pharmacologically relevant doses of AA tightly recapitulated the rearrangement of cell subpopulations and the gene expression changes happening in pemetrexed -treated cultures and related to chemoresistance. Further, we showed that release of AA following pemetrexed treatment was due to cPLA2 and that AA signaling impinged on NFkB activation and largely affected anchorage-independent, 3D growth and the resistance of the MPM 3D cultures to the drug. Conclusions AA is an early mediator of the adaptive response to pem in chemoresistant MPM and, possibly, other malignancies.

Characterization of hematopoietic lineage-specific gene expression by ES cell in vitro differentiation induction system

Blood ◽  
2000 ◽  
Vol 95 (3) ◽  
pp. 870-878 ◽  
Author(s):  
Takumi Era ◽  
Toshiaki Takagi ◽  
Tomomi Takahashi ◽  
Jean-Christophe Bories ◽  
Toru Nakano
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Embryonic Stem ◽  
Experimental System ◽  
Specific Gene ◽  
Specific Gene Expression ◽  
Differentiation Induction ◽  
Lineage Specific Gene ◽  
Megakaryocytic Cell

The continuous generation of mature blood cells from hematopoietic progenitor cells requires a highly complex series of molecular events. To examine lineage-specific gene expression during the differentiation process, we developed a novel method combiningLacZ reporter gene analysis with in vitro hematopoietic differentiation induction from mouse embryonic stem cells. For a model system using this method, we chose the erythroid and megakaryocytic differentiation pathways. Although erythroid and megakaryocytic cells possess distinct functional and morphologic features, these 2 lineages originate from bipotential erythro-megakaryocytic progenitors and share common lineage-restricted transcription factors. A portion of the 5′ flanking region of the human glycoprotein IIb (IIb) integrin gene extending from base −598 to base +33 was examined in detail. As reported previously, this region is sufficient for megakaryocyte-specific gene expression. However, previous reports that used human erythro-megakaryocytic cell lines suggested that one or more negative regulatory regions were necessary for megakaryocyte-specific gene expression. Our data clearly showed that an approximately 200-base enhancer region extending from −598 to −400 was sufficient for megakaryocyte-specific gene expression. This experimental system has advantages over those using erythro-megakaryocytic cell lines because it recapitulates normal hematopoietic cell development and differentiation. Furthermore, this system is more efficient than transgenic analysis and can easily examine gene expression with null mutations of specific genes.

scholarly journals miR-195-5p Suppresses the Proliferation, Migration, and Invasion of Oral Squamous Cell Carcinoma by Targeting TRIM14

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Tong Wang ◽  
Yipeng Ren ◽  
Ruixun Liu ◽  
Juntao Ma ◽  
Yueyi Shi ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Squamous Cell ◽  
Migration And Invasion ◽  
Specific Gene ◽  
Invasion And Migration ◽  
And Migration

MicroRNAs (miRNAs) play an essential role in tumor biological processes through interacting with specific gene targets. The involvement of miR-195-5p in cell proliferation, invasion, and migration has been demonstrated in several cancer cell lines, while its function in oral squamous cell carcinoma (OSCC) remains unclear. Here we find that miR-195-5p expression is lower in OSCC than in nontumor tissues, while its overexpression in cell lines can lead to the promotion of apoptosis and the reduction of cell growth, migration, and invasion. Moreover, we identify the tripartite motif-containing protein (TRIM14) as a target of miR-195-5p. Therefore, we reason that the tumor suppressor role of miR-195-5p in OSCC is dependent on the interaction with TRIM14.

scholarly journals STAT3 and STAT5 Activation in Solid Cancers

2019 ◽  
Author(s):  
Sebastian Igelmann ◽  
Heidi A. Neubauer ◽  
Gerardo Ferbeyre
Keyword(s):  
Tumor Suppressor ◽  
Molecular Mechanisms ◽  
Control Cell ◽  
Cytokine Signaling ◽  
Specific Gene ◽  
Sumo Ligase ◽  
Mitochondrial Functions ◽  
Cancer Mutations ◽  
Context Dependent

The Signal Transducer and Activator of Transcription (STAT)3 and 5 are activated by many cytokine receptors to regulate specific gene expression and mitochondrial functions. Their role in cancer is largely context dependent as they can both act as oncogenes and tumor suppressors. We review here the role of STAT3/5 activation in solid cancers and summarize their association to survival in cancer patients. The molecular mechanisms that underpins the oncogenic activity of STAT3/5 signaling includes the regulation of genes that control cell cycle, cell death, inflammation and stemness. In addition, STAT3 mitochondrial functions are required for transformation. On the other hand, several tumor suppressor pathways act on or are activated by STAT3/5 signaling including the p19ARF/p53 pathway, tyrosine phosphatases, suppressor of cytokine signaling 1 and 3, the sumo ligase PIAS3, the E3 ubiquitin ligase TMF/ARA160 and the miRNAs miR-124 and miR-1181. Cancer mutations and epigenetic alterations may alter the balance between pro-oncogenic and tumor suppressor activities associated to STAT3/5 signaling explaining their context dependent association to tumor progression both in human cancers and animal models.

MicroRNA-544 down-regulates both Bcl6 and Stat3 to inhibit tumor growth of human triple negative breast cancer

2016 ◽  
Vol 397 (10) ◽  
pp. 1087-1095 ◽  
Author(s):  
Zhengzhi Zhu ◽  
Shengying Wang ◽  
Jinhai Zhu ◽  
Qifeng Yang ◽  
Huiming Dong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Migration And Invasion ◽  
Specific Gene ◽  
Potential Biomarker ◽  
Mouse Xenograft Model

Abstract Triple negative breast cancer lacking estrogen receptor (ER), progesterone receptor and Her2 account for account for the majority of the breast cancer deaths, due to the lack of specific gene targeted therapy. Our current study aimed to investigate the role of miR-544 in triple negative breast cancer. Endogenous levels of miR-544 were significantly lower in breast cancer cell lines than in human breast non-tumorigenic and mammary epithelial cell lines. We found that miR-544 directly targeted the 3′-untranslated region (UTR) on both Bcl6 and Stat3 mRNAs, and overexpression of miR-544 in triple negative breast cancer cells significantly down-regulated expressions of Bcl6 and Stat3, which in turn severely inhibited cancer cell proliferation, migration and invasion in vitro. Employing a mouse xenograft model to examine the in vivo function of miR-544, we found that expression of miR-544 significantly repressed the growth of xenograft tumors. Our current study reported miR-544 as a tumor-suppressor microRNA particularly in triple negative breast cancer. Our data supported the role of miR-544 as a potential biomarker in developing gene targeted therapies in the clinical treatment of triple negative breast cancer.

TSGA10 Expression Status in Breast Cancer: The Role of Microenvironmental Changes

2020 ◽  
Author(s):  
Marzieh Marzbany ◽  
Amir Hossein Norooznezhad ◽  
Zohreh Hoseinkhani ◽  
Azadeh Mahnam ◽  
Kiumaras Eslampia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Specific Gene ◽  
Mcf 7

Abstract Background: Testis-specific gene antigen (TSGA10) mainly involves in spermatogenesis and embryogenesis. In the new defined roles, being a tumor suppressor agent or a cancer/testis antigen (CTA) is still unclear for this protein. The current study aimed to examine exact role of TSGA10 as a tumor suppressor or CTA in breast cancer and evaluate the role of microenvironment on its expression. Methods: This study evaluated the expression of TSGA10 and hypoxia-inducible factor 1α (HIF-1α) in two different breast cancer cell lines (MCF-7 and MDA-MB23) as well as their control (MCF10A) using real-time PCR. Moreover, expression of the mentioned genes evaluated in samples obtained from tumoral tissues with two types of controls: paired (tumor-free margin) and unpaired (healthy individuals). Also, in order to asses TSGA10 levels in the tumoral tissues, western blotting was performed. Furthermore, to evaluate the role epigenetic changes on TSGA10 expression, breast cancer cell lines were treated with a histone deacetylase inhibitor (HDACI) as well as H2O2 for oxidative stress induction. Results: The current study evaluated 36 patients diagnosed with breast cancer as well as 10 healthy controls. According to the results, it was shown that 35 (97.7%) and 1 (2.8%) of patients were diagnosed with ductal and lobular carcinomas respectively. The TSGA10 levels in the tumoral samples showed 1.38±0.014-fold decrease and 1.41±0.127-fold increase compared with their paired (P<0.001) and unpaired (P<0.001) controls respectively. Moreover, results of blotting in tumoral tissues expressed significant decrease in TSGA10 levels in comparison to the paired controls (P<0.01). Among the cell lines, TSGA10 expression in MCF-7 and MDA-MB23 cells had 4.9±0.283 and 4.21±0.163 folds of decrease in normoxic and 4.7±.0.283 and 7.1±0.141 folds of expression reduction in hypoxic condition respectively (all P<0.0001). Furthermore, the results showed that HIF-1α expression was up-regulated in both normoxic (P<0.01) and hypoxic (P<0.01) conditions. Also, TSGA10 expression increased up to 7.39±0.156 folds in MCF-7 cells after HDACI treatment (all P<0.01). However, MDA-MB23 cells firstly experienced a decrease and then a notable increase in TSGA10 expression (all P<0.01). Conclusion: Results of current study showed that TSGA10 seems to be tumor suppressor, however, further studies are necessary.

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