A Novel sLRP6E1E2 Inhibits Canonical Wnt Signaling, Epithelial-to-Mesenchymal Transition, and Induces Mitochondria-Dependent Apoptosis in Lung Cancer

Lee, Jung Sun; Hur, Man Wook; Lee, Seong Kyung; Choi, Won‐Il; Kwon, Young Guen; Yun, Chae Ok

doi:10.1371/journal.pone.0036520

Cited by 27 publications

(29 citation statements)

References 38 publications

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“…Phosphate‐buffered saline (PBS) was the negative control. Tumor volume was calculated according to the formula: V = 0.52 × a 2 × b , where a is the smallest superficial diameter; and b , the largest superficial diameter …”

Section: Methodsmentioning

confidence: 99%

Human Noxin is an anti‐apoptotic protein in response to DNA damage of A549 non‐small cell lung carcinoma

Won

Yun

et al. 2013

Intl Journal of Cancer

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Human Noxin (hNoxin, C11Orf82), a homolog of mouse noxin, is highly expressed in colorectal and lung cancer tissues. hNoxin contains a DNA-binding C-domain in RPA1, which mediates DNA metabolic processes, such as DNA replication and DNA repair. Expression of hNoxin is associated with S phase in cancer cells and in normal cells. Expression of hNoxin was induced by ultraviolet (UV) irradiation. Knockdown of hNoxin caused growth inhibition of colorectal and lung cancer cells. The comet assay and western blot analysis revealed that hNoxin knockdown induced apoptosis through activation of p38 mitogenactivated protein kinase (MAPK)/p53 in non-small cell lung carcinoma A549 cells. Furthermore, simultaneous hNoxin knockdown and treatment with DNA-damaging agents, such as camptothecin (CPT) and UV irradiation, enhanced apoptosis, whereas Trichostatin A (TSA) did not. However, transient overexpression of hNoxin rescued cells from DNA damage-induced apoptosis but did not block apoptosis in the absence of DNA damage. These results suggest that hNoxin may be associated with inhibition of apoptosis in response to DNA damage. An adenovirus expressing a short hairpin RNA against hNoxin transcripts significantly suppressed the growth of A549 tumor xenografts, indicating that hNoxin knockdown has in vivo anti-tumor efficacy. Thus, hNoxin is a DNA damage-induced anti-apoptotic protein and potential therapeutic target in cancer.

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Section: Methodsmentioning

confidence: 99%

Human Noxin is an anti‐apoptotic protein in response to DNA damage of A549 non‐small cell lung carcinoma

Won

Yun

et al. 2013

Intl Journal of Cancer

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“…Aberrant activation of WNT/β-catenin has been associated with poor prognosis clinically [14]. On the other hand, downregulation of WNT signaling inhibited NSCLC cell proliferation and xenograft growth, reduced cell motility and invasion, and induced a more differentiated phenotype [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Role of MiR-3619-5p in β-Catenin-Mediated Non-Small Cell Lung Cancer Growth and Invasion

Niu

Liu

et al. 2015

Cell Physiol Biochem

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Background/Aims: The malignancy of non-small cell lung cancer (NSCLC) is largely due to its fast growth and invasion. WNT/β-catenin signaling plays a critical role in regulating NSCLC carcinogenesis. Hence, suppression of β-catenin signal transduction in NSCLC cells may improve the therapeutic outcome. Methods: We analyzed the levels of β-catenin and miR-3619-5p in NSCLC specimens, compared to paired non-tumor normal lung tissue (NT). We did Bioinformatics analyses on the binding sites of 3'-UTR of β-catenin mRNA by miR-3619-5p. We modified the levels of miR-3619-5p in NSCLC cells and examined their effects on β-catenin levels, and on the growth and invasion of NSCLC cells in an MTT assay and a transwell cell migration assay, respectively. Results: NSCLC specimens had significant higher levels of β-catenin, and significantly lower levels of miR-3619-5p, compared to NT. The levels of β-catenin and miR-3619-5p were inversely correlated in NSCLC specimens. Bioinformatics analyses showed that miR-3619-5p bound to 3'-UTR of β-catenin mRNA in NSCLC cells to inhibit its translation. Overexpression of miR-3619-5p decreased β-catenin protein, while depletion of miR-3619-5p increased β-catenin protein in NSCLC cells, without altering β-catenin mRNA levels. Overexpression of miR-3619-5p in NSCLC cells inhibited cell growth and invasion, while depletion of miR-3619-5p in NSCLC lines increased cell growth and invasion. Conclusion: Our data demonstrate a previously unappreciated role for miR-3619-5p in suppression of β-catenin-mediated cancer growth and invasion in NSCLC cells, and highlight miR-3619-5p as a novel cancer suppressor in NSCLC.

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“…S1A). GFP‐expressing Ad under the control of the cytomegalovirus (CMV) promoter (dCMV‐GFP) was used as a control …”

Section: Methodsmentioning

confidence: 99%

Potent antitumor effect of tumor microenvironment‐targeted oncolytic adenovirus against desmoplastic pancreatic cancer

Hong

et al. 2017

Intl Journal of Cancer

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Pancreatic cancer is a leading cause of cancer-related death. Desmoplastic pancreatic tumors exhibit excessive extracellular matrix (ECM) and are thus highly resistant to anticancer therapeutics, since the ECM restricts drug penetration and dispersion. Here, we designed and generated two hypoxia-responsive and cancer-specific hybrid promoters, H(mT)E and H(E)mT. Transgene expression driven by each hybrid promoter was markedly higher under hypoxic conditions than normoxic conditions. Moreover, H(E)mT-driven transgene expression was highly cancer-specific and was superior to that of H(mT)E-driven expression. A decorin-expressing oncolytic adenovirus (Ad; oH(E)mT-DCN) replicating under the control of the H(E)mT promoter induced more potent and highly cancer-specific cell death compared with its cognate control oncolytic Ad, which harbored the endogenous Ad E1A promoter. Moreover, oH(E)mT-DCN exhibited enhanced antitumor efficacy compared with both the clinically approved oncolytic Ad ONYX-015 and its cognate control oncolytic Ad lacking DCN. oH(E)mT-DCN treatment also attenuated the expression of major ECM components, such as collagen I/III, elastin and fibronectin and induced tumor cell apoptosis, leading to extensive viral dispersion within orthotopic pancreatic tumors and pancreatic cancer patient-derived tumor spheroids. Collectively, these findings demonstrate that oH(E)mT-DCN exhibits potent antitumor efficacy by degrading the ECM and inducing apoptosis in a multifunctional process. This process facilitates the dispersion and replication of oncolytic Ad, making it an attractive candidate for the treatment of aggressive and desmoplastic pancreatic cancer.Pancreatic cancer is the fourth leading cause of cancerrelated death in Europe and the United States.1 Only 10-20% of all patients with pancreatic cancer are resectable at presentation. The US National Cancer Institute recently reported that the overall 5-year relative survival rate for 2002-2008 was 5.8%, and nearly 90% of all patients were dead 1 year after diagnosis, with a median survival of <6 months. 2,3 One experimental treatment option of particular interest for pancreatic cancer is oncolytic virotherapy, which uses viral vectors to preferentially replicate in tumor cells and induce cancer cell death. Among the various viral vectors that have been tested, adenovirus (Ad) has been most extensively used in gene therapy applications, and sufficient data from randomized clinical trials support its safety in patients. 4-6Although oncolytic Ad-mediated cancer gene therapy is highly promising, significant therapeutic efficacy of oncolytic Ad for the treatment of localized tumors has not yet been achieved in clinical trials; thus, further improvements are needed. 7,8 Hypoperfusion and desmoplasia are two prominent features of pancreatic cancer that attenuate the therapeutic efficacy of cancer therapeutics.9 Aberrant extracellular matrix (ECM) functions as a protective layer that prevents drug penetration and diffusion into the pancreatic tumors, contributing t...

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A Novel sLRP6E1E2 Inhibits Canonical Wnt Signaling, Epithelial-to-Mesenchymal Transition, and Induces Mitochondria-Dependent Apoptosis in Lung Cancer

Cited by 27 publications

References 38 publications

Human Noxin is an anti‐apoptotic protein in response to DNA damage of A549 non‐small cell lung carcinoma

Human Noxin is an anti‐apoptotic protein in response to DNA damage of A549 non‐small cell lung carcinoma

Role of MiR-3619-5p in β-Catenin-Mediated Non-Small Cell Lung Cancer Growth and Invasion

Potent antitumor effect of tumor microenvironment‐targeted oncolytic adenovirus against desmoplastic pancreatic cancer

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