Reduced cell proliferation by IKK2 depletion in a mouse lung-cancer model

Xia, Yifeng; Narayana, Y.; Leblanc, Mathias; Ke, Eugene; Zhang, Yonghui; Oldfield, Eric; Shaw, Reuben J.; Verma, Inder M.

doi:10.1038/ncb2428

Cited by 136 publications

(173 citation statements)

References 49 publications

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“…The intratracheal instillation of the CA2-Cre lentivirus, at a dose of 10 5 lentiviral particles, into LSL-KRas mice generated adenomas and adenocarcinoma with a latency of up to 12 mo (Fig. S1A) (17,18). When combined with knockdown of Tp53 by shRNA (pLV-CA2-Cre-shP53), generation of lung adenocarcinoma was significantly accelerated (3-4 mo) and led to decreased survival (4-6 mo) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously developed a mouse model of lung cancer by lentiviral delivery of Cre recombinase, activating the KRas G12D mutant allele in LoxpStop-Loxp-KRas G12D (LSL-KRas) mice in a lung epitheliumspecific manner (18). These mice also contain the LSL-luciferase allele and express Cre-dependent luciferase expression.…”

Section: Resultsmentioning

confidence: 99%

“…Mice with the KRas G12D allele develop benign adenomatous lesions with long latency to develop adenocarcinoma (17,18). A combination of Tp53 deletion and KRas G12D activation leads to significant reduction in latency and generates aggressive lung adenocarcinoma (7,18,19). Further, KRas G12D cooperates with deletion of other tumor suppressors (5) to develop lung adenocarcinoma, such as Lkb1 (20), Pten (21), and P19Arf (22) in genetic mouse models.…”

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confidence: 99%

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confidence: 99%

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Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

Narayana

Xia

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Lung adenocarcinoma, a major form of non-small cell lung cancer, is the leading cause of cancer deaths. The Cancer Genome Atlas analysis of lung adenocarcinoma has identified a large number of previously unknown copy number alterations and mutations, requiring experimental validation before use in therapeutics. Here, we describe an shRNA-mediated high-throughput approach to test a set of genes for their ability to function as tumor suppressors in the background of mutant KRas and WT Tp53. We identified several candidate genes from tumors originated from lentiviral delivery of shRNAs along with Cre recombinase into lungs of Loxp-stop-Loxp-KRas mice. Ephrin receptorA2 (EphA2) is among the top candidate genes and was reconfirmed by two distinct shRNAs. By generating knockdown, inducible knockdown and knockout cell lines for loss of EphA2, we showed that negating its expression activates a transcriptional program for cell proliferation. Loss of EPHA2 releases feedback inhibition of KRAS, resulting in activation of ERK1/2 MAP kinase signaling, leading to enhanced cell proliferation. Intriguingly, loss of EPHA2 induces activation of GLI1 transcription factor and hedgehog signaling that further contributes to cell proliferation. Small molecules targeting MEK1/2 and Smoothened hamper proliferation in EphA2-deficient cells. Additionally, in EphA2 WT cells, activation of EPHA2 by its ligand, EFNA1, affects KRAS–RAF interaction, leading to inhibition of the RAS-RAF-MEK-ERK pathway and cell proliferation. Together, our studies have identified that (i) EphA2 acts as a KRas cooperative tumor suppressor by in vivo screen and (ii) reactivation of the EphA2 signal may serve as a potential therapeutic for KRas-induced human lung cancers.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

Narayana

Xia

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Although TIMP1 shows paradoxical effects on tumour growth and metastasis 32,33 , and very little is known about its mode of secretion, we demonstrate that hRAB37 directs TIMP1 secretion in a nucleotide-dependent manner to inhibit tumour metastasis attributing to its MMP inhibitor activity. In agreement, TIMP1 inhibits the invasion and metastasis of malignant tumour cells mainly owing to its role as an inhibitor of MMPs 34,35 .…”

Section: Wt-timp1kd +Timp1mentioning

confidence: 96%

Small GTPase Rab37 targets tissue inhibitor of metalloproteinase 1 for exocytosis and thus suppresses tumour metastasis

et al. 2014

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Rab small GTPases are master regulators of membrane trafficking and guide vesicle targeting. Recent publications show that Rab-controlled trafficking pathways are altered during tumorigenesis. However, whether any of the Rabs plays a metastasis suppressor role is least explored. Here we address the metastasis suppressive function of human Rab37 (hRAB37) using secretomics, cell, animal and clinical analyses. We show that tissue inhibitor of metalloproteinase 1 (TIMP1), a secreted glycoprotein that inhibits extracellular matrix turnover, is a novel cargo of hRAB37. hRAB37 regulates the exocytosis of TIMP1 in a nucleotide-dependent manner to inactivate matrix metalloproteinase 9 (MMP9) migration axis in vitro and in vivo. Dysfunction of hRAB37 or TIMP1 abrogates metastasis suppression. Lung cancer patients with metastasis and poor survival show low hRAB37 protein expression coinciding with low TIMP1 in tumours. Our findings identify hRAB37 as a novel metastasis suppressor Rab that functions through the TIMP1-MMP9 pathway and has significant prognostic power.

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TFF1 antagonizes TIMP‐1 mediated proliferative functions in gastric cancer

Omar

Soutto

Bhat

et al. 2018

Molecular Carcinogenesis

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Tissue inhibitor matrix metalloproteinase-1 (TIMP1) is one of four identified members of the TIMP family. We evaluated the role of TIMP1 in gastric cancer using human and mouse tissues along with gastric organoids and in vitro cell models. Using quantitative real-time RT-PCR, we detected significant overexpression of TIMP1 in the human gastric cancer samples, as compared to normal stomach samples (P < 0.01). We also detected overexpression of Timp1 in neoplastic gastric lesions of the Tff1-knockout (KO) mice, as compared to normal stomach tissues. Reconstitution of TFF1 in human gastric cancer cell lines led to a significant decrease in the mRNA expression level of TIMP1 (P < 0.05). In vitro analysis demonstrated that TIMP1 mRNA expression is induced by TNF-α and activation of NF-κB whereas inhibition of NF-κB using BAY11-7082 led to inhibition of NF-κB and downregulation of TIMP1. Western blot analysis confirmed the decrease in TIMP1 protein level following reconstitution of TFF1. By using immunofluorescence, we showed nuclear localization of NF-κB and expression of TIMP1 in gastric organoids established from the Tff1-KO stomach where reconstitution of Tff1 using recombinant protein led to a notable reduction in the expression of both NF-κB and TIMP1. Using EDU assay, as a measure of proliferating cells, we found that TIMP1 promotes cellular proliferation whereas TFF1 reconstitution leads to a significant decrease in cellular proliferation (P < 0.05). In summary, our findings demonstrate overexpression of TIMP1 in mouse and human gastric cancers through NF-kB-dependent mechanism. We also show that TFF1 suppresses NF-κB and inhibits TIMP1-mediated proliferative potential in gastric cancer.

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Reduced cell proliferation by IKK2 depletion in a mouse lung-cancer model

Cited by 136 publications

References 49 publications

Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

Small GTPase Rab37 targets tissue inhibitor of metalloproteinase 1 for exocytosis and thus suppresses tumour metastasis

TFF1 antagonizes TIMP‐1 mediated proliferative functions in gastric cancer

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