microRNA
            ‐100 functions as a tumor suppressor in non‐small cell lung cancer via regulating epithelial‐mesenchymal transition and Wnt/β‐catenin by targeting
            HOXA1

10506 Background: DEAR1, also known as TRIM62, maps to 1p.35, a genomic interval within which loss of heterozygosity occurs at high frequency in carcinomas. DEAR1 has been proposed as a regulator of cell polarity in vitro. Methods: We genetically engineered mice lacking DEAR1 alleles at murine chromosome 4. To study the impact of DEAR1 loss in lung cancer, DEAR1 deficient mice were crossed to mice carrying the latent mutant K-rasG12D allele (K-rasLA1). Results: No survival difference was observed between DEAR1+/─ and DEAR1─/─ mice (729 vs 699 days, p=0.98) but they were markedly shorter than that of DEAR1 wild-type littermates (803 days, p=0.01). Over 90% of mice developed tumors, mainly adenocarcinomas, including invasive and/or metastatic lung cancer in 23% of cases. DEAR1-deficient K-rasLA1 mice had reduced life span compared with DEAR1+/+:K-ras+/LA1 littermates (184 vs 291 days, p<0.0001). The survival of DEAR1+/─:K-ras+/LA1 and DEAR1─/─:K-ras+/LA1 mice were similar (180 vs 153 days, p=0.38) and qPCR and IHC analyses suggested loss of the wild-type DEAR1 allele. The survival of DEAR1-deficient K-rasLA1 mice was also shorter than that of control p53+/─:K-ras+/LA1 mice (240 days; p=0.01). The metastasis incompetent K-rasLA1–positive LKR13 cell line after shRNA DEAR1 knock-down and cell lines derived from DEAR1-deficient K-rasLA1 tumors recapitulated an invasive phenotype in transwell migration and 3D culture assays and a metastatic phenotype on SC or IV injection into immunocompetent wild-type littermates. The latter was associated with epithelial-mesenchymal transition involving loss of E-cadherin and DEAR1 expression and upregulation of vimentin, Twist, and CD44. DEAR1 downregulation was very prevalent in a non-small cell lung cancer (NSCLC) tissue array with 214 samples. Patients with early stage NSCLC and loss of DEAR1 expression had a markedly shorter time to relapse compared to those retaining DEAR1 expression (5.1 vs 2.87 years, p=0.049) and worse 5-year relapse-free and overall survival rates. Conclusions: DEAR1 is a novel tumor suppressor that negatively regulates EMT and promotes lung cancer metastasis. DEAR1 loss is a poor prognostic factor in NSCLC.

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ARHGAP10 inhibits the epithelial–mesenchymal transition of non-small cell lung cancer by inactivating PI3K/Akt/GSK3β signaling pathway

Cancer Cell International ◽

10.1186/s12935-021-02022-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Lan-Lan Lin ◽

Fan Yang ◽

Dong-Huan Zhang ◽

Cong Hu ◽

Sheng Yang ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Signaling Pathway ◽

Cell Lung Cancer ◽

Rho Gtpase ◽

Epithelial Mesenchymal Transition ◽

Essential Element ◽

Small Cell ◽

Small Cell Lung ◽

Mesenchymal Transition

Abstract Background Rho GTPase activating protein 10 (ARHGAP10) has been implicated as an essential element in multiple cellular process, including cell migration, adhesion and actin cytoskeleton dynamic reorganization. However, the correlation of ARHGAP10 expression with epithelial–mesenchymal transition (EMT) in lung cancer cells is unclear and remains to be elucidated. Herein, we investigated the relationship between the trait of ARHGAP10 and non-small cell lung cancer (NSCLC) pathological process. Methods Immunohistochemistry was conducted to evaluate the expression of ARHGAP10 in NSCLC tissues. CCK-8 assays, Transwell assays, scratch assays were applied to assess cell proliferation, invasion and migration. The expression levels of EMT biomarkers and active molecules involved in PI3K/Akt/GSK3β signaling pathway were examined through immunofluorescence and Western blot. Results ARHGAP10 was detected to be lower expression in NSCLC tissues compared with normal tissues from individuals. Moreover, overexpression of ARHGAP10 inhibited migratory and invasive potentials of A549 and NCI-H1299 cells. In addition, ARHGAP10 directly mediated the process of EMT via PI3K/Akt/GSK3β pathway. Meanwhile, activation of the signaling pathway of insulin-like growth factors-1 (IGF-1) reversed ARHGAP10 overexpression regulated EMT in NSCLC cells. Conclusion ARHGAP10 inhibits the epithelial–mesenchymal transition in NSCLC via PI3K/Akt/GSK3β signaling pathway, suggesting agonist of ARHGAP10 may be an optional remedy for NSCLC patients than traditional opioids.

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PP4R1 interacts with HMGA2 to promote non‐small‐cell lung cancer migration and metastasis via activating MAPK/ERK‐induced epithelial‐mesenchymal transition

Molecular Carcinogenesis ◽

10.1002/mc.23168 ◽

2020 ◽

Vol 59 (5) ◽

pp. 467-477

Author(s):

Bin Wang ◽

Lin‐Yue Pan ◽

Ning Kang ◽

Xiao‐Yong Shen

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Epithelial Mesenchymal Transition ◽

Small Cell ◽

Small Cell Lung ◽

Mesenchymal Transition ◽

Cancer Migration

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456 Involvement of Matrix Metalloproteinases in Epithelial-mesenchymal Transition and Metastasis of Small-cell Lung Cancer

European Journal of Cancer ◽

10.1016/s0959-8049(12)71129-2 ◽

2012 ◽

Vol 48 ◽

pp. S109

Author(s):

T.D. Ahrens ◽

A. Krohn ◽

M. Follo ◽

S. Wollner ◽

M. Burger

Keyword(s):

Lung Cancer ◽

Matrix Metalloproteinases ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Epithelial Mesenchymal Transition ◽

Small Cell ◽

Small Cell Lung ◽

Mesenchymal Transition

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Upregulation of IL-11, an IL-6 Family Cytokine, Promotes Tumor Progression and Correlates with Poor Prognosis in Non-Small Cell Lung Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000488166 ◽

2018 ◽

Vol 45 (6) ◽

pp. 2213-2224 ◽

Cited By ~ 19

Author(s):

Meng Zhao ◽

Yahui Liu ◽

Ran Liu ◽

Jin Qi ◽

Yongwang Hou ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Poor Prognosis ◽

Epithelial Mesenchymal Transition ◽

Small Cell ◽

Small Cell Lung ◽

Mesenchymal Transition

Background/Aims: Cytokines are key players in tumorigenesis and are potential targets in cancer treatment. Although IL-6 has attracted considerable attention, interleukin 11 (IL-11), another member of the IL-6 family, has long been overlooked, and little is known regarding its specific function in non-small cell lung cancer (NSCLC). In this study, we explored IL-11’s role in NSCLC and the detailed mechanism behind it. Methods: Cell proliferation in response to IL-11 was determined by colony formation, BrdU incorporation and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. Cell motility was measured by Transwell and wound healing assays. NSCLC xenograft models were used to confirm oncogenic function of IL-11 in vivo. Immunohistochemical staining and western blot assay were performed to detect epithelial–mesenchymal transition (EMT) markers and cell signaling pathway alterations. Eighteen NSCLC patients and 5 normal lung samples were collected together with data from an online database to determine the link between IL-11 expression and malignant progression. Results: We observed that IL-11 was upregulated in NSCLC samples compared with normal tissue samples and correlated with poor prognosis. Data from in vitro and in vivo models indicated that IL-11 promotes cell proliferation and tumorigenesis. Cell migration and invasion were also enhanced by IL-11. Epithelial–mesenchymal transition (EMT) was also observed after IL-11 incubation. Furthermore, IL-11 activated AKT and STAT3 in our experimental models. In addition, we observed that hypoxia induced IL-11 expression in NSCLC cells. Deferoxamine (DFX) or dimethyloxalylglycine (DMOG) induced hypoxia-inducible factor 1-alpha (HIF1α) upregulation, which enhanced IL-11 expression in NSCLC cells. Conclusions: Taken together, our results indicate that IL-11 is an oncogene in NSCLC, and elucidating the mechanism behind it may provide insights for NSCLC treatment.

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