p21 Ablation in Liver Enhances DNA Damage, Cholestasis, and Carcinogenesis

Ehedego, Haksier; Boekschoten, Mark V.; Hu, Wei Shou; Doler, Carina; Haybaeck, Johannes; Gaβler, Nikolaus; Müller, Michael; Liedtke, Christian

doi:10.1158/0008-5472.can-14-1356

Cited by 31 publications

(26 citation statements)

References 36 publications

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“…5A and B). Consistent with the FACS data, the expression of G1/S phase checkpoint proteins, including tumor suppressor p53 (P53) (34), cell cycle regulator p21 (P21) (35) and plasminogen activator inhibitor 1 (PAI-1) (36) were markedly upregulated in the cells infected with LV-RP5-833A20.1 (Fig. 5C).…”

Section: Rp5-833a201 Inhibits Cell Cycle Progression and Induces Celsupporting

confidence: 83%

Long non-coding RNA RP5-833A20.1 inhibits proliferation, metastasis and cell cycle progression by suppressing the expression of NFIA in U251 cells

Kang

Nie

et al. 2016

Molecular Medicine Reports

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Abstract. Early reports suggest that nuclear factor IA (NFIA) is important in the pathogenesis of glioma. Our previous study demonstrated that the long non-coding RNA (lncRNA), RP5-833A20.1, suppressed the expression of NFIA in THP-1 macrophage-derived foam cells. However, the effect and possible mechanism of RP5-833A20.1 on glioma remains to be fully elucidated, and whether the NFIA-dependent pathway is involved in its progression has not been investigated. In the present study, the mechanisms by which RP5-833A20.1 regulates the expression of NFIA in glioma were investigated. The expression levels of RP5-833A20.1 and NFIA were determined in U251 cells and clinical samples using reverse transcription-quantitative polymerase chain reaction (PCR) analysis. The effects of RP5-833A20.1 on cell proliferation, invasion, cell cycle and apoptosis were evaluated using in vitro assays. The potential changes in protein expression were investigated using western blot analysis. The methylation status of the CpG island in the NFIA promoter was determined using bisulfite PCR (BSP) sequencing. It was found that the expression of RP5-833A20.1 was downregulated, whereas the expression of NFIA was upregulated in glioma tissues, compared with corresponding adjacent nontumor tissues from 20 patients with glioma. The overexpression of RP5-833A20.1 inhibited proliferation and cell cycle progression, and induced apoptosis in the U251 cells. The mRNA and protein levels of NFIA were markedly inhibited by overexpression of RP5-833A20.1 in the U251 cells. The overexpression of RP5-833A20.1 increased the expression of microRNA-382-5p in the U251 cells. The BSP assay revealed that the overexpression of RP5-833A20.1 enhanced the methylation level of the NFIA promoter. These results demonstrated that RP5-833A20.1 inhibited tumor cell proliferation, induced apoptosis and inhibited cell-cycle progression by suppressing the expression of NFIA in U251 cells. Collectively, these results indicated RP5-833A20.1 as a novel therapeutic target for glioma.

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Section: Rp5-833a201 Inhibits Cell Cycle Progression and Induces Celsupporting

confidence: 83%

Long non-coding RNA RP5-833A20.1 inhibits proliferation, metastasis and cell cycle progression by suppressing the expression of NFIA in U251 cells

Kang

Nie

et al. 2016

Molecular Medicine Reports

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“…26 In papillomas, NF-κβ and the axis of ROCK2/FAK/β-catenin 5,6 may contribute to the demise of p53, given both NF-κβ 26 and FAK-associated β-catenin 38,46 inhibit p53 expression. These papilloma data thus link NF-κβ with increased DNA mutations/chromosomal instability 25,39 following p53 loss and associated p21 inhibition 47 [below]; and indirectly link ROCK2-mediated NF-κβ to stromal remodelling 25 thus accounting for effects previously observed on expression of ECM molecules such as tenascin C. 48,49 One consequence of p53 loss leading to an altered matrix may involve downregulated microRNAs, 34 such as miR-200 which regulates cell-cell adhesion molecules 35 and effected ROCK signalling in gastric cancer. 36 Of note, p53-mediated miR-200 expression depended upon AKT levels, 37 consistent with p53 loss driving malignant conversion in trigenic HK1.ras/fos/Pten flx carcinogenesis.…”

Section: Discussionmentioning

confidence: 75%

“…This latter result not only shows the requirement for ROCK er -mediated NF-κβ expression to facilitate progression, but also demonstrated that p21 responses eliminated NF-κβ expression independent of ROCK2 signalling. 44,47 Furthermore, down-regulation of NF-κβ paralleled increasing basal layer p53 expression 26 which restored the p21/p53-mediated resistance to malignant conversion. 20,23 Indeed, this direct p21-mediated antagonism to NF-κβ signalling was recently demonstrated in liver carcinogenesis where p21 knockout was shown to be pivotal to progression following loss of NEMO, a major NF-kβ pathway regulator.…”

Section: Discussionmentioning

confidence: 95%

“…20,23 Indeed, this direct p21-mediated antagonism to NF-κβ signalling was recently demonstrated in liver carcinogenesis where p21 knockout was shown to be pivotal to progression following loss of NEMO, a major NF-kβ pathway regulator. 47 Of relevance to K14.ROCK er /HK1.ras 1205 carcinogenesis, p21 overexpression protected NEMO Dhepa animals against DNA damage, 39,41 whereas p21 knockout accelerated hepato-carcinogenesis in bi-genic NEMO Dhepa /p21 null mice, 47 thus implicating NF-κβ in chromosomal damage. 33,39,41,45 Most major consequences of ROCK2 activation alter the tumour microenvironment and establish a context permissive for stage-specific progression.…”

Section: Discussionmentioning

confidence: 99%

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ROCK2/rasHa co-operation induces malignant conversion via p53 loss, elevated NF-κB and tenascin C-associated rigidity, but p21 inhibits ROCK2/NF-κB-mediated progression

et al. 2016

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ROCK2/rasHa cooperation induce malignant conversion via p53 loss, elevated NF-κβ and tenascin C-associated rigidity but p21 inhibits ROCK2/NF-κβ-mediated progression. Oncogene, 36, pp. 2529Oncogene, 36, pp. -2542Oncogene, 36, pp. . (doi:10.1038Oncogene, 36, pp. /onc.2016 This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/129163/ Malignancy depended on ROCK er /p-Mypt1 expression, as cessation of 4HT-treatment induced disorganised tissue architecture and p21-associated differentiation in wdSCCs; yet tenascin C retention in connective tissue ECM suggests the rigidity laid down for conversion persists. Novel papilloma outgrowths appeared expressing intense, basal-layer p21 which confined endogenous ROCK2/p-Mypt1/NF-κβ to supra-basal layers, and was paralleled by restored basal-layer p53. In later SCCs, 4HT-cessation became irrelevant as endogenous ROCK2 expression increased, driving progression via p21 loss, elevated NF-κβ expression and tenascin C-associated rigidity; with p-Mypt1 inactivation/actinomyosin-mediated contractility to facilitate invasion. However, p21-associated inhibition of early-stage malignant progression and the intense expression in papilloma outgrowths, identifies a novel, significant antagonism between p21 and ras Ha /ROCK2/NF-κβ signalling in skin 3 carcinogenesis. Collectively these data show that ROCK2 activation induces malignancy in ras Ha -initiated/promoted papillomas in the context of p53 loss and novel NF-κβ expression; whilst increased tissue rigidity and cell motility/contractility help mediate tumour progression.4

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“…One of the best-known p53 target genes is p21, which regulates cell survival [36] and protects cells against apoptosis [37]. Western blot analysis showed a time-dependent expression of the KLK6, p21, and p53 levels after AF treatment in NCI-N87 and SNU-620 cells when compared to AF-sensitive cells, suggesting a role for these proteins in AF-induced cell death (Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

Kallikrein-related peptidase 6 induces chemotherapeutic resistance by attenuating auranofin-induced cell death through activation of autophagy in gastric cancer

et al. 2016

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Kallikrein-related peptidase 6 (KLK6) is a biomarker of gastric cancer associated with poor prognosis. Mechanisms by which KLK6 could be exploited for chemotherapeutic use are unclear. We evaluated auranofin (AF), a compound with cytotoxic effects, in KLK6-deficient cells, and we investigated whether KLK6 expression induces autophagy and acquisition of drug resistance in gastric cancer. Using cultured human cells and a mouse xenograft model, we investigated how KLK6 affects antitumor-reagent-induced cell death and autophagy. Expression levels of KLK6, p53, and autophagy marker LC3B were determined in gastric cancer tissues. We analyzed the effects of knockdown/overexpression of KLK6, LC3B, and p53 on AF-induced cell death in cancer cells. Increased KLK6 expression in human gastric cancer tissues and cells inhibited AF-induced cell motility due to increased autophagy and p53 levels. p53 dependent induction of KLK6 expression increased autophagy and drug resistance, whereas KLK6 silencing decreased the autophagy level and increased drug sensitivity. During AF-induced cell death, KLK6 and LC3B colocalized to autophagosomes, associated with p53, and were then trafficked to the cytosol. In the xenograft model of gastric cancer, KLK6 expression decreased AF-induced cell death and KLK6-induced autophagy increased AF resistance. Taken together, the data suggest that the induction of autophagic processes through KLK6 expression may increase acquisition of resistance to AF. Our findings may contribute to a new paradigm for tumor therapeutics.

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p21 Ablation in Liver Enhances DNA Damage, Cholestasis, and Carcinogenesis

Cited by 31 publications

References 36 publications

Long non-coding RNA RP5-833A20.1 inhibits proliferation, metastasis and cell cycle progression by suppressing the expression of NFIA in U251 cells

Long non-coding RNA RP5-833A20.1 inhibits proliferation, metastasis and cell cycle progression by suppressing the expression of NFIA in U251 cells

ROCK2/rasHa co-operation induces malignant conversion via p53 loss, elevated NF-κB and tenascin C-associated rigidity, but p21 inhibits ROCK2/NF-κB-mediated progression

Kallikrein-related peptidase 6 induces chemotherapeutic resistance by attenuating auranofin-induced cell death through activation of autophagy in gastric cancer

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