DEK Depletion Negatively Regulates Rho/ROCK/MLC Pathway in Non–Small Cell Lung Cancer

Wang, Junying; Sun, Liankun; Yang, Mingyue; Luo, Wenting; Gao, Ying; Liu, Zihui; Qiu, Xueshan; Wang, Enhua

doi:10.1369/0022155413488120

Cited by 19 publications

(21 citation statements)

References 30 publications

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“… 65 , 66 Interestingly, DEK loss was recently shown to negatively regulate Rho signaling in non-small cell lung cancer. 67 In addition to lung metastases, we observed that Dek expression significantly promoted invasion in transwell assays in multiple murine breast cancer cell lines and in primary HNSCC cells ( Figure S6D ), which agrees with previous reports in human breast and lung cancer and indicates that DEK-mediated invasion is relevant to several cancer types. 29 , 32 Of interest, breast patient data associated high DEK expression with an increased risk for distant metastasis in previously node-negative patients.…”

Section: Discussionsupporting

confidence: 92%

The DEK oncogene promotes cellular proliferation through paracrine Wnt signaling in Ron receptor-positive breast cancers

et al. 2014

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Disease progression and recurrence are major barriers to surviving breast cancer. Understanding the etiology of recurrent or metastatic breast cancer and underlying mechanisms is critical for the development of new treatments and improved survival. Here, we report that two commonly over-expressed breast cancer oncogenes, Ron and DEK, cooperate to promote advanced disease through multi-pronged effects on β-catenin signaling. The Ron receptor is commonly activated in breast cancers, and Ron over-expression in human disease stimulates β-catenin nuclear translocation and is an independent predictor of metastatic dissemination. Dek is a chromatin-associated oncogene whose expression has been linked to cancer through multiple mechanisms, including β-catenin activity. We demonstrate here that Dek is a downstream target of Ron receptor activation in murine and human models. The absence of Dek in the MMTV-Ron mouse model led to a significant delay in tumor development, characterized by decreased cell proliferation, diminished metastasis, and fewer cells expressing cancer stem cell markers. Dek complementation of cell lines established from this model was sufficient to promote cellular growth and invasion in vitro and in vivo. Mechanistically, Dek expression stimulated the production and secretion of Wnt ligands to sustain an autocrine/paracrine canonical β-catenin signaling loop. Finally, we show that Dek over-expression promotes tumorigenic phenotypes in immortalized human mammary epithelial MCF10A cells and, in the context of Ron receptor activation, correlates with disease recurrence and metastasis in patients. Overall, our studies demonstrate that DEK over-expression, due in part to Ron receptor activation, drives breast cancer progression through the induction of Wnt/β-catenin signaling.

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Section: Discussionsupporting

confidence: 92%

The DEK oncogene promotes cellular proliferation through paracrine Wnt signaling in Ron receptor-positive breast cancers

et al. 2014

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“…Few studies to date have reported an association between DEK expression and clinicopathological parameters, as well as the DEK prognostic role in lung cancer. Wang et al analyzed DEK immunohistochemistry in 112 NSCLC cases and reported that DEK-positive tumors were correlated with poor differentiation, advanced p-TNM stage and nodal metastasis, and DEK expression in lung adenocarcinoma was significantly higher compared with DEK expression in squamous cell carcinoma (31). In the present study, qRT-PCR and western blot data demonstrated that the levels of DEK mRNA and protein were significantly higher in NSCLC samples compared with adjacent non-tumor tissues.…”

Section: Discussionsupporting

confidence: 56%

“…CEA level and the smoking status of patients with NSCLS (P>0.05). However, Wang et al reported that DEK expression was significantly related to nodal metastasis and pathological subtype (31). The causes for the differences in results may be due to case selection, the source of the antibody used or staining method.…”

Section: Discussionmentioning

confidence: 99%

Significance of DEK overexpression for the prognostic evaluation of non-small cell lung carcinoma

Liu

Qi³

et al. 2015

Oncology Reports

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In the present study, we explored the role of DEK expression for the prognostic evaluation of non-small cell lung carcinoma (NSCLC). DEK protein and mRNA expression levels were detected in NSCLC cells and fresh tissue samples of NSCLC paired with adjacent non-tumor tissues, respectively. NSCLC cases (n=196) meeting strict follow-up criteria were selected for immunohistochemical staining of DEK protein. Correlations between DEK expression and clinicopathological features of the NSCLC cases were evaluated using Chi-square tests. Survival rates were calculated using the Kaplan-Meier method, and the relationship between prognostic factors and patient overall survival was analyzed using Cox proportional hazard analysis. Based on the results, the levels of DEK protein and mRNA were significantly upregulated in 6 fresh tissue samples of NSCLC. Immunohistochemical analysis showed that the DEK expression rate was significantly higher in the NSCLC samples compared with either the adjacent non-tumor tissues or normal lung tissues. DEK expression was correlated with poor differentiation and late pathological stage of NSCLC. DEK expression was also correlated with low disease-free survival and overall survival rates. In the early-stage group, disease-free and overall survival rates of patients with DEK expression were significantly lower than those of patients without DEK expression. Further analysis using a Cox proportional hazard regression model revealed that DEK expression emerged as a significant independent hazard factor for the overall survival rate of patients with NSCLC. Consequently, DEK plays an important role in the progression of NSCLC. DEK may potentially be used as an independent biomarker for the prognostic evaluation of NSCLC.

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“…As the Rho/ROCK pathway has been found to be involved in the progression and metastasis of several types of cancer (28,29), we further investigated its implication and showed that miR-145 has a suppressive effect on U87 cell invasion, at least partially by downregulating the RhoA/ROCK1 pathway. Notably, we found that miR-145 not only inhibits ROCK1 gene and protein expression, but also downregulates the expression of the upstream small GTPase RhoA at the protein level, indicating that ROCK1 may have diverse effects on the functional balance of small GTPases.…”

Section: Discussionmentioning

confidence: 99%

ROCK1, a novel target of miR-145, promotes glioma cell invasion

Wan

Cheng

Peng

et al. 2014

Molecular Medicine Reports

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Malignant glioma is the most common type of cancer in the central nervous system, with highly invasive characteristics. The Rho-associated protein kinase (ROCK1) has been found to act as key regulator of actin cytoskeleton reorganization, a process closely associated with cancer cell invasion. microRNA-145 (miRNA-145) has been recently shown to act as a suppressor in several types of tumor, including glioma. However, the exact regulatory mechanism by which miR-145 inhibits glioma still remains to be uncovered. In this study, we report that the miR-145 level was significantly reduced in glioma tissues and in the human glioma cell lines U87 and U251, as compared to matched adjacent and normal brain tissues. We then identified the ROCK1 gene as a novel target of miR-145. The expression of ROCK1 was markedly upregulated in glioma tissues, as well as in U87 and U251 cells. Moreover, miR-145 significantly inhibited ROCK1 protein expression in U87 cells. We further show that miR-145 transfection considerably reduced the invasive ability of U87 cells, and was accompanied by the downregulation of matrix metalloproteinase 2 and 9, an effect which could be attenuated by overexpression of ROCK1. In conclusion, the present study suggests that miR-145 can inhibit U87 glioma cell invasion, at least partially via downregulation of the RhoA/ROCK1 pathway. In conclusion, this is the first study to report that ROCK1, as a novel target of miR-145, acts as a positive regulator of glioma cell invasion. Therefore, ROCK1 may constitute a promising target for glioma treatment.

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DEK Depletion Negatively Regulates Rho/ROCK/MLC Pathway in Non–Small Cell Lung Cancer

Cited by 19 publications

References 30 publications

The DEK oncogene promotes cellular proliferation through paracrine Wnt signaling in Ron receptor-positive breast cancers

The DEK oncogene promotes cellular proliferation through paracrine Wnt signaling in Ron receptor-positive breast cancers

Significance of DEK overexpression for the prognostic evaluation of non-small cell lung carcinoma

ROCK1, a novel target of miR-145, promotes glioma cell invasion

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