Insulinoma-associated protein 1 controls nasopharyngeal carcinoma to radiotherapy by modulating cyclin D1-dependent DNA repair machinery

2019 ◽  
Vol 41 (3) ◽  
pp. 326-333 ◽  
Author(s):  
Ruibiao Song ◽  
Xing Wei ◽  
You Wang ◽  
Shousen Hu ◽  
Yunpeng Ba ◽  
...  
Keyword(s):  
Dna Repair ◽  
Nasopharyngeal Carcinoma ◽  
Cell Survival ◽  
Cyclin D1 ◽  
Poor Prognosis ◽  
Genetic Manipulation ◽  
Molecular Target ◽  
Transcriptional Factor ◽  
Xenograft Mice

AbstractInsulinoma-associated protein 1 (INSM1), a zinc finger transcriptional factor, is proven to be deregulated in several types of cancers. However, comprehension of the molecular mechanism of INSM1-mediated tumor progression remains poor. Here, we show that the radioresistant nasopharyngeal carcinoma (NPC) patients have higher expressions of INSM1 that correlated with poor prognosis. Genetic manipulation of INSM1 expression sufficiently controls the response of NPC cells to irradiation (IR). Mechanistically, cells exposed to IR, increased intracellular INSM1 competitively disrupts the interaction of cyclin D1 and CDK4 resulting in cell survival by the cyclin D1-dependent DNA repair machinery. Moreover, knockdown of INSM1 sensitives NPC cells to IR in vivo and protects xenograft mice from mortality. Taken together, these results indicate that INSM1 modulates NPC to radiotherapy by controlling cyclin D1-dependent DNA repair machinery that could be manipulated as a novel molecular target for NPC therapy.

Differential response of prostate cancer cells to ionizing radiation: The RB status.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 106-106
Author(s):  
Robert Benjamin Den ◽  
Steve Ciment ◽  
Ankur Sharma ◽  
Hestia Mellert ◽  
Steven McMahon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Ionizing Radiation ◽  
Cell Survival ◽  
Hormone Sensitive ◽  
Clonogenic Cell ◽  
Castrate Resistant

106 Background: Prostate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer death in U.S. men. The retinoblastoma tumor suppressor protein, RB, plays a critical role in cell cycle regulation and loss of RB has been observed in 25-30% of prostate cancers. We have previously shown that RB loss results in a castrate resistant phenotype, however the consequences of RB status with regard to radiation response are unknown. We hypothesized that RB loss would downregulate the G1-S cell cycle checkpoint arrest normally induced by irradiation, inhibit DNA repair, and subsequently sensitize cells to ionizing radiation. Methods: Experimental work was performed with multiple isogenic prostate cancer cell lines (hormone sensitive: LNCaP and LAP-C4 cells and hormone resistant C42, 22Rv1 cells; stable knockdown of RB using shRNA). Gamma H2AX assays were used to quantitate DNA damage and PARP cleavage and Caspase 3 were used to quantitate apoptosis. FACS analysis with BrdU was used to assess the cell cycle. Cell survival was measured using the clonogenic cell survival assay. In vivo work was performed in nude mice with tumor xenografts. Results: We observed that loss of RB increased radioresponsiveness in both transient and clonogenic cell survival assays in both hormone sensitive and castrate resistant cell lines (p<0.05). Cell death was not mediated through increased apoptosis nor was perturbations in cell cycle noted. However, loss of RB effected DNA repair as measured by gamma H2AX staining as well as cellular senescence. In vivo xenografts of the RB deficient tumors exhibited diminished tumor mass, lower PSA kinetics and decreased tumor growth after treatment with single fraction of ionizing radiation in comparison to RB intact tumors (p<0.05). Conclusions: Loss of RB results in a differential response to ionizing radiation. Isogenic cells with RB knockdown are more sensitive to DNA damage and result in reduced cell survival. The underlying mechanism appears to be related to DNA damage repair and cellular senescence.

TSLP-Induced Alterations of Multiple Signaling Pathways in Primary CRLF2 B-ALL Xenografts

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3783-3783
Author(s):  
Parveen Shiraz ◽  
Olivia Francis ◽  
Ineavely Delgado ◽  
Shannalee R Martinez ◽  
Jacqueline Coats ◽  
...  
Keyword(s):  
Gene Expression ◽  
Poor Prognosis ◽  
Mtor Pathway ◽  
Receptor Complex ◽  
Ras Pathway ◽  
Disease Mechanisms ◽  
Pathway Activation ◽  
Altered Glucose ◽  
Xenograft Mice

Abstract B-cell acute lymphoblastic leukemia (B-ALL) with genetic defects leading to overexpression of CRLF2 (CRLF2 B-ALL) is associated with a high relapse rate and poor prognosis. CRLF2 B-ALL comprises approximately half of the high risk B-ALL characterized by a gene expression profile that is similar to that of Philadelphia chromosome-positive ALL (Ph-like B-ALL). In pediatric patients, CRLF B-ALL occurs 5 times more frequently among children of Hispanic and Native American ethnicity and is a major contributor to health disparities in ALL. CRLF2 (cytokine related ligand factor 2) together with the IL-7 receptor alpha chain, forms a receptor complex that is activated by the cytokine, TSLP (Thymic Stromal Lymphopoietin). Activation of CRLF by TSLP leads to downstream JAK-STAT5 and mTOR pathway phosphorylation even in CRLF2 B-ALL harboring activating JAK mutations. We found that primary human marrow (BM) stromal cells express TSLP (RT-PCR and ELISA) and thus provide an in vivo source of TSLP to activate CRLF2 B-ALL cells. Our next step was to develop a xenograft model system to identify the in vivo CRLF2-mediated gene expression profile and disease mechanisms that might contribute to poor prognosis. Unlike most other cytokines, mouse TSLP is species-specific and thus does not activate the human CRLF2 receptor complex. We engineered immune-deficient NOD/SCID IL-2Rγ null (NSG) mice to express normal serum levels (~20 pg/ml) of human TSLP (hTSLP+ mice), as well as control mice that lack human TSLP (hTSLP– mice). Primary human CRLF2 B-ALL were injected into hTSLP+ and hTSLP– mice and expanded for 10 weeks in vivo. Whole genome microarray was performed on CRLF2 B-ALL cells isolated by magnetic separation from the BM of hTSLP+ and hTSLP- xenograft mice. Evaluation of microarray data by Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis showed that genes downstream of mTOR pathway activation were upregulated in hTSLP+ as compared to hTSLP- mice, confirming hTSLP activity in the hTSLP+ xenograft mice. Microarray identified 280 genes that are upregulated and 281 genes that are downregulated (> 1.7 fold; p<.05) in vivo in leukemia cells from hTSLP+ as compared to hTSLP– mice. GSEA and Ingenuity Pathway Analysis of these data show increased RAS pathway activation and altered glucose metabolism in CRLF2 B-ALL from hTSLP+ as compared to hTSLP– mice. In addition to increased mTOR pathway activation, these gene expression data implicate altered glucose metabolism and increased RAS pathway activation as potential contributors to the poor prognosis in CRLF2 B-ALL. The hTSLP+ CRLF2 B-ALL xenograft mice described here provide a novel preclinical model for studying disease mechanisms and identifying therapies to target signaling pathways activated by TSLP in CRLF2 B-ALL. Disclosures No relevant conflicts of interest to declare.

scholarly journals LINC00210 as a miR-328-5p sponge promotes nasopharyngeal carcinoma tumorigenesis by activating NOTCH3 pathway

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Shu Zhang ◽  
Ping Li ◽  
Lei Zhao ◽  
Ling Xu
Keyword(s):  
Cell Proliferation ◽  
Nasopharyngeal Carcinoma ◽  
Tumor Growth ◽  
Signaling Pathway ◽  
Untranslated Region ◽  
Poor Prognosis ◽  
Noncoding Rnas ◽  
Proliferation And Invasion

As a kind of essential regulators, long noncoding RNAs (lncRNAs) have attracted a lot of attention in recent years. Nevertheless, the function of lncRNA in nasopharyngeal carcinoma (NPC) remains poorly understood. In the present study, we explained the role and mechanism of LINC00210 in NPC progression. We found that LINC00210 expression was up-regulated in NPC samples. Besides, its overexpression was positively correlated with NPC metastasis while predicting poor prognosis. Based on functional experiments, we revealed that LINC00210 contributed to NPC cell proliferation and invasion in vitro, and promotes tumor growth in vivo. Mechanistically, we identified that LINC00210 was located in the cytoplasm of NPC cells and served as the miR-328-5p sponge. Furthermore, we showed that miR-328-5p targets the 3′ untranslated region (3′-UTR) of NOTCH3. Through inhibiting miR-328-5p activity, LINC00210 promoted NOTCH3 expression in NPC, leading to activation of NOTCH3 signaling pathway. In conclusion, our study indicates LINC00210 promotes NPC progression through modulating proliferation and invasion.

Improvement of effectiveness in maize breeding

2006 ◽  
Vol 54 (3) ◽  
pp. 351-358 ◽  
Author(s):  
P. Pepó
Keyword(s):  
Recurrent Selection ◽  
Genetic Manipulation ◽  
Field Testing ◽  
Tissue Cultures ◽  
Maize Breeding ◽  
Breeding Programmes ◽  
Speed Up ◽  
Selection For

Plant regeneration via tissue culture is becoming increasingly more common in monocots such as maize (Zea mays L.). Pollen (gametophytic) selection for resistance to aflatoxin in maize can greatly facilitate recurrent selection and the screening of germplasm for resistance at much less cost and in a shorter time than field testing. In vivo and in vitro techniques have been integrated in maize breeding programmes to obtain desirable agronomic attributes, enhance the genes responsible for them and speed up the breeding process. The efficiency of anther and tissue cultures in maize and wheat has reached the stage where they can be used in breeding programmes to some extent and many new cultivars produced by genetic manipulation have now reached the market.

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