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  • 1
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    Online Resource
    Somatic A‐to‐I RNA‐edited RHOA isoform 2 specific‐R176G mutation promotes tumor progression in lung adenocarcinoma
    Wiley ; 2023
    In:  Molecular Carcinogenesis Vol. 62, No. 3 ( 2023-03), p. 348-359
    Details
    In: Molecular Carcinogenesis, Wiley, Vol. 62, No. 3 ( 2023-03), p. 348-359
    Abstract: Adenosine‐to‐inosine (A‐to‐I) RNA editing is the most common posttranscriptional editing to create somatic mutations and increase proteomic diversity. However, the functions of the edited mutations are largely underexplored. To identify novel targets in lung adenocarcinoma (LUAD), we conducted a genome‐wide somatic A‐to‐I RNA editing analysis of 23 paired adjacent normal and LUAD transcriptomes and identified 26,280 events, including known nonsynonymous AZIN1‐S367G and novel RHOAiso2 (RHOA isoform 2)‐R176G, tubulin gamma complex associated protein 2 (TUBGCP2)‐N211S, and RBMXL1‐I40 M mutations. We validated the edited mutations in silico in multiple databases and in newly collected LUAD tissue pairs with the SEQUENOM MassARRAY® and TaqMan PCR Systems. We selected RHOAiso2‐R176G due to its significant level, isoform‐specificity, and being the most common somatic edited nonsynonymous mutation of RHOAiso2 to investigate its roles in LUAD tumorigenesis. RHOAiso2 is a ubiquitous but low‐expression alternative spliced isoform received a unique Alu‐rich exon at the 3′ RHOA mRNA to become an editing RNA target, leading to somatic hypermutation and protein diversity. Interestingly, LUAD patients harboring the RHOAiso2‐R176G mutation were associated with aberrant RHOA functions, cancer cell proliferation and migration, and poor clinical outcomes in transcriptome analysis. Mechanistically, RHOAiso2‐R176G mutation‐expressing LUAD cells potentiate RHOA‐guanosine triphosphate (GTP) activity to phosphorylate ROCK1/2 effectors and enhance cell proliferation and migration in vitro and increase tumor growth in xenograft and systemic metastasis models in vivo. Taken together, the RHOAiso2‐R176G mutation is a common somatic A‐to‐I edited mutation of the hypermutated RHOA isoform 2. It is an oncogenic and isoform‐specific theranostic target that activates RHOA‐GTP/p‐ROCK1/2 signaling to promote tumor progression.
    Type of Medium: Online Resource
    ISSN: 0899-1987 , 1098-2744
    URL: Issue
    URL: Article
    DOI: 10.1002/mc.v62.3
    DOI: 10.1002/mc.23490
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2001984-1
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  • 2
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    miR-103/107 Promote Metastasis of Colorectal Cancer by Targeting the Metastasis Suppressors DAPK and KLF4
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 14 ( 2012-07-15), p. 3631-3641
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 14 ( 2012-07-15), p. 3631-3641
    Abstract: Metastasis is the major cause of poor prognosis in colorectal cancer (CRC), and increasing evidence supports the contribution of miRNAs to cancer progression. Here, we found that high expression of miR-103 and miR-107 (miR-103/107) was associated with metastasis potential of CRC cell lines and poor prognosis in patients with CRC. We showed that miR-103/107 targeted the known metastasis suppressors death-associated protein kinase (DAPK) and Krüppel-like factor 4 (KLF4) in CRC cells, resulting in increased cell motility and cell–matrix adhesion and decreased cell–cell adhesion and epithelial marker expression. miR-103/107 expression was increased in the presence of hypoxia, thereby potentiating DAPK and KLF4 downregulation and hypoxia-induced motility and invasiveness. In mouse models of CRC, miR-103/107 overexpression potentiated local invasion and liver metastasis effects, which were suppressed by reexpression of DAPK or KLF4. miR-103/107–mediated downregulation of DAPK and KLF4 also enabled the colonization of CRC cells at a metastatic site. Clinically, the signature of a miR-103/107 high, DAPK low, and KLF4 low expression profile correlated with the extent of lymph node and distant metastasis in patients with CRC and served as a prognostic marker for metastasis recurrence and poor survival. Our findings therefore indicate that miR-103/107–mediated repression of DAPK and KLF4 promotes metastasis in CRC, and this regulatory circuit may contribute in part to hypoxia-stimulated tumor metastasis. Strategies that disrupt this regulation might be developed to block CRC metastasis. Cancer Res; 72(14); 3631–41. ©2012 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-12-0667
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
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    Online Resource
    PSPC1 is a new contextual determinant of aberrant subcellular translocation of oncogenes in tumor progression
    Springer Science and Business Media LLC ; 2021
    In:  Journal of Biomedical Science Vol. 28, No. 1 ( 2021-12)
    Details
    In: Journal of Biomedical Science, Springer Science and Business Media LLC, Vol. 28, No. 1 ( 2021-12)
    Abstract: Dysregulation of nucleocytoplasmic shuttling is commonly observed in cancers and emerging as a cancer hallmark for the development of anticancer therapeutic strategies. Despite its severe adverse effects, selinexor, a selective first-in-class inhibitor of the common nuclear export receptor XPO1, was developed to target nucleocytoplasmic protein shuttling and received accelerated FDA approval in 2019 in combination with dexamethasone as a fifth-line therapeutic option for adults with relapsed refractory multiple myeloma (RRMM). To explore innovative targets in nucleocytoplasmic shuttling, we propose that the aberrant contextual determinants of nucleocytoplasmic shuttling, such as PSPC1 (Paraspeckle component 1), TGIF1 (TGF-β Induced Factor Homeobox 1), NPM1 (Nucleophosmin), Mortalin and EBP50, that modulate shuttling (or cargo) proteins with opposite tumorigenic functions in different subcellular locations could be theranostic targets for developing anticancer strategies. For instance, PSPC1 was recently shown to be the contextual determinant of the TGF-β prometastatic switch and PTK6/β-catenin reciprocal oncogenic nucleocytoplasmic shuttling during hepatocellular carcinoma (HCC) progression. The innovative nucleocytoplasmic shuttling inhibitor PSPC1 C-terminal 131 polypeptide (PSPC1-CT131), which was developed to target both the shuttling determinant PSPC1 and the shuttling protein PTK6, maintained their tumor-suppressive characteristics and exhibited synergistic effects on tumor suppression in HCC cells and mouse models. In summary, targeting the contextual determinants of nucleocytoplasmic shuttling with cargo proteins having opposite tumorigenic functions in different subcellular locations could be an innovative strategy for developing new therapeutic biomarkers and agents to improve cancer therapy.
    Type of Medium: Online Resource
    ISSN: 1423-0127
    URL: Article
    DOI: 10.1186/s12929-021-00753-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 1482918-6
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  • 4
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    PSPC1 Potentiates IGF1R Expression to Augment Cell Adhesion and Motility
    MDPI AG ; 2020
    In:  Cells Vol. 9, No. 6 ( 2020-06-18), p. 1490-
    Details
    In: Cells, MDPI AG, Vol. 9, No. 6 ( 2020-06-18), p. 1490-
    Abstract: Paraspeckle protein 1 (PSPC1) overexpression in cancers is known to be the pro-metastatic switch of tumor progression associated with poor prognosis of cancer patients. However, the detail molecular mechanisms to facilitate cancer cell migration remain elusive. Here, we conducted integrated analysis of human phospho-kinase antibody array, transcriptome analysis with RNA-seq, and proteomic analysis of protein pulldown to study the molecular detail of PSPC1-potentiated phenotypical transformation, adhesion, and motility in human hepatocellular carcinoma (HCC) cells. We found that PSPC1 overexpression re-assembles and augments stress fiber formations to promote recruitment of focal adhesion contacts at the protruding edge to facilitate cell migration. PSPC1 activated focal adhesion-associated kinases especially FAK/Src signaling to enhance cell adhesion and motility toward extracellular matrix (ECM). Integrated transcriptome and gene set enrichment analysis indicated that PSPC1 modulated receptor tyrosine kinase IGF1R involved in the focal adhesion pathway and induction of diverse integrins expression. Knockdown IGF1R expression and treatment of IGF1R inhibitor suppressed PSPC1-induced cell motility. Interestingly, knockdown PSPC1-interacted paraspeckle components including NONO, FUS, and the lncRNA Neat1 abolished PSPC1-activated IGF1R expression. Together, PSPC1 overexpression induced focal adhesion formation and facilitated cell motility via activation of IGF1R signaling. PSPC1 overexpression in tumors could be a potential biomarker of target therapy with IGF1R inhibitor for improvement of HCC therapy.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells9061490
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2661518-6
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  • 5
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    Paraquat increases connective tissue growth factor and collagen expression via angiotensin signaling pathway in human lung fibroblasts
    Elsevier BV ; 2010
    In:  Toxicology in Vitro Vol. 24, No. 3 ( 2010-4), p. 803-808
    Details
    In: Toxicology in Vitro, Elsevier BV, Vol. 24, No. 3 ( 2010-4), p. 803-808
    Type of Medium: Online Resource
    ISSN: 0887-2333
    URL: Article
    DOI: 10.1016/j.tiv.2009.12.015
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2010
    detail.hit.zdb_id: 1501079-X
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  • 6
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    Online Resource
    Chymase mediates paraquat-induced collagen production in human lung fibroblasts
    Elsevier BV ; 2010
    In:  Toxicology Letters Vol. 193, No. 1 ( 2010-03), p. 19-25
    Details
    In: Toxicology Letters, Elsevier BV, Vol. 193, No. 1 ( 2010-03), p. 19-25
    Type of Medium: Online Resource
    ISSN: 0378-4274
    URL: Article
    DOI: 10.1016/j.toxlet.2009.12.001
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2010
    detail.hit.zdb_id: 1500784-4
    SSG: 12
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  • 7
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    Online Resource
    Downregulation of Caveolin-1 in a Murine Model of Acute Allergic Airway Disease
    Elsevier BV ; 2011
    In:  Pediatrics & Neonatology Vol. 52, No. 1 ( 2011-02), p. 5-10
    Details
    In: Pediatrics & Neonatology, Elsevier BV, Vol. 52, No. 1 ( 2011-02), p. 5-10
    Type of Medium: Online Resource
    ISSN: 1875-9572
    URL: Article
    DOI: 10.1016/j.pedneo.2010.12.006
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2011
    detail.hit.zdb_id: 2441821-3
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  • 8
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    Online Resource
    Activation of the Renin-Angiotensin System in Hyperoxia-Induced Lung Fibrosis in Neonatal Rats
    S. Karger AG ; 2012
    In:  Neonatology Vol. 101, No. 1 ( 2012), p. 47-54
    Details
    In: Neonatology, S. Karger AG, Vol. 101, No. 1 ( 2012), p. 47-54
    Abstract: 〈 i 〉 Background: 〈 /i 〉 Oxygen toxicity plays an important role in lung injury and may lead to bronchopulmonary dysplasia. We previously demonstrated that hyperoxia activated the renin-angiotensin system (RAS) in cultured human fetal lung fibroblasts. 〈 i 〉 Objective: 〈 /i 〉 To examine whether the upregulation of RAS components is associated with hyperoxia-induced lung fibrosis in neonatal Sprague-Dawley rats. 〈 i 〉 Methods: 〈 /i 〉 Experimental rat pups were exposed to 1 week of 〉 95% O 〈 sub 〉 2 〈 /sub 〉 and a further 2 weeks of 60% O 〈 sub 〉 2 〈 /sub 〉 . Control pups were exposed to room air over the same periods. Lung tissues were taken for biochemical and histochemical assays on postnatal days 7 and 21. 〈 i 〉 Results: 〈 /i 〉 Hyperoxia significantly increased total collagen content and the expression of type I collagen and alpha smooth muscle actin when compared to control rats. RAS components including angiotensinogen, angiotensin-converting enzyme, angiotensin II, and angiotensin II type 1 receptor were significantly upregulated by hyperoxia. The results also demonstrated that only the extracellular signal-regulated kinase (ERK) signaling pathway was activated by hyperoxia exposure. p38 mitogen-activated protein kinase and c-Jun N-terminal kinase were not activated. 〈 i 〉 Conclusions: 〈 /i 〉 Local RAS activation is involved in the pathogenesis of hyperoxia-induced lung fibrosis in neonatal rats. ERK phosphorylation might mediate angiotensin II type 1 receptor activation.
    Type of Medium: Online Resource
    ISSN: 1661-7800 , 1661-7819
    URL: Article
    DOI: 10.1159/000329451
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2012
    detail.hit.zdb_id: 2403535-X
    SSG: 12
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  • 9
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    Oligohydramnios Decreases Platelet-Derived Growth Factor Expression in Fetal Rat Lungs
    S. Karger AG ; 2007
    In:  Neonatology Vol. 92, No. 3 ( 2007), p. 187-193
    Details
    In: Neonatology, S. Karger AG, Vol. 92, No. 3 ( 2007), p. 187-193
    Abstract: 〈 i 〉 Objective: 〈 /i 〉 To evaluate the effects ofexperimental oligohydramnios on lung growth, expression of platelet-derived growth factor (PDGF) and its receptors, and lung morphology in fetal rats. 〈 i 〉 Methods: 〈 /i 〉 On day 16 of gestation, we anesthetized timed pregnant Sprague-Dawley dams and punctured uterine wall and fetal membranes of each uterine sac which resulted in oligohydramnios. The fetuses in the opposite uterine horn served as controls. On days 19 and 21 of gestation, the fetuses were delivered by cesarean section and weighed, and the lungs were dissected free and weighed. 〈 i 〉 Results: 〈 /i 〉 Rats exposed to oligohydramnios exhibited significantly lower lung/body weight ratios on days 19 and 21 of gestation and significantly lower radial saccular counts on day 21 of gestation than did the control rats. Lung PDGF-A and PDGF-B gene and protein expression and elastin level were significantly decreased in rats exposed to oligohydramnios on days 19 and 21 of gestation. The PDGF receptor alpha and beta gene expression levels were significantly decreased in rats exposed to oligohydramnios on day 19 of gestation. 〈 i 〉 Conclusion: 〈 /i 〉 A decreased PDGF expression may be important in the pathogenesis of oligohydramnios-induced pulmonary hypoplasia and suggests that supplementation may provide useful therapeutic strategies.
    Type of Medium: Online Resource
    ISSN: 1661-7800 , 1661-7819
    URL: Article
    DOI: 10.1159/000102958
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2007
    detail.hit.zdb_id: 2403535-X
    SSG: 12
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  • 10
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    Online Resource
    Effects of Activated Protein C on Ventilator-Induced Lung Injury in Rats
    S. Karger AG ; 2010
    In:  Respiration Vol. 80, No. 3 ( 2010), p. 246-253
    Details
    In: Respiration, S. Karger AG, Vol. 80, No. 3 ( 2010), p. 246-253
    Abstract: 〈 i 〉 Background: 〈 /i 〉 Mechanical ventilation with a high tidal volume (V 〈 i 〉 T 〈 /i 〉 ) increases lung and systemic plasminogen activator inhibitor (PAI)-1 levels and alveolar fibrin deposition. Activated protein C (APC) may decrease PAI activity in endothelial cell-conditioned medium and thus enhance fibrinolysis. 〈 i 〉 Objectives: 〈 /i 〉 The aims of this study were to test the hypothesis that APC can neutralize PAI-1 activity and improve lung function in an animal model of ventilator-induced lung injury. 〈 i 〉 Methods: 〈 /i 〉 Rats were ventilated with a high-volume zero positive end-expiratory pressure (PEEP; HVZP) protocol by a volume-cycled ventilator for 2 h at a V 〈 i 〉 T 〈 /i 〉 of 30 ml/kg, a respiratory rate of 25 breaths/min, and an Fi 〈 i 〉 O 〈 /i 〉 〈 sub 〉 2 〈 /sub 〉 of 0.21. Fifteen minutes before ventilation, the rats received intravenous APC (250 µg/kg, HVZP+APC group) or normal saline (vehicle; HVZP group). Another group that received no ventilation served as the control group. 〈 i 〉 Results: 〈 /i 〉 Levels of arterial blood gas tension were comparable between the two ventilation groups throughout the study period. Rats treated with the HVZP protocol exhibited significantly higher total protein and macrophage inflammatory protein-2 concentrations in bronchoalveolar lavage fluid (BALF) and higher lung PAI-1 mRNA expression and plasma active PAI-1 levels than did the control group. Administration of APC tended to reduce the BALF protein content and systemic PAI-1 activity but did not improve the lung histology in the HVZP+APC group. Plasma levels of D-dimers were comparable among the three study groups. 〈 i 〉 Conclusions: 〈 /i 〉 These results suggest that APC administered at a higher dosage might improve lung function by reducing alveolar protein leakage and systemic coagulation.
    Type of Medium: Online Resource
    ISSN: 0025-7931 , 1423-0356
    URL: Article
    DOI: 10.1159/000279438
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2010
    detail.hit.zdb_id: 1464419-8
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