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Diethylnitrosamine induces lung adenocarcinoma in FVB/N mouse.

ABSTRACT: Diethylnitrosamine is a well known carcinogen that induces cancers of various organs in mice and rats. Using FVB/N mouse strain, here we show that diethylnitrosamine induces primarily lung adenocarcinomas with modest tumor development in the liver, offering a new model to study chemical carcinogenesis in the lung.Animals were exposed to a single high dose of diethylnitrosamine, and more than 70% of the mice developed lung cancer. To obtain a new transplantable tumor line, pieces of primary tumors were inoculated and maintained subcutaneously in the same mouse strain. We used immunohistochemistry to characterize the tumor for main lung adenocarcinoma markers. We searched for mutations in KRAS exon 2 and EGFR exon 19, 21 with Sanger sequencing. We also compared the normal lung tissue with the diethylnitrosamine induced primary adenocarcinoma, and with the subcutaneously maintained adenocarcinoma using Western blot technique for main cell cycle markers and to identify the main pathways.Primary and subcutaneous tumors express cytokeratin-7 and thyroid transcription factor-1, markers characteristic to lung adenocarcinoma. In addition, no mutations were found in the hot spot regions of KRAS and EGFR genes. We found high mTOR activation, but the level of p-Akt Ser473 and p-Akt Thr308 decreased in the tumorous samples.We established a new lung adenocarcinoma model using FVB/N mouse strain and diethylnitrosamine. We believe that this new model system would be highly useful in lung cancer research.

SUBMITTER: Mervai Z

PROVIDER: S-EPMC5803903 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Diethylnitrosamine induces lung adenocarcinoma in FVB/N mouse.

Mervai Zsolt Z Egedi Krisztina K Kovalszky Ilona I Baghy Kornélia K

BMC cancer 20180207 1

<h4>Background</h4>Diethylnitrosamine is a well known carcinogen that induces cancers of various organs in mice and rats. Using FVB/N mouse strain, here we show that diethylnitrosamine induces primarily lung adenocarcinomas with modest tumor development in the liver, offering a new model to study chemical carcinogenesis in the lung.<h4>Methods</h4>Animals were exposed to a single high dose of diethylnitrosamine, and more than 70% of the mice developed lung cancer. To obtain a new transplantable ...[more]

PMID: 29415661

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Project description:Objective: Explore the mechanism of CaSR's involvement in bone metastasis in lung adenocarcinoma. Methods: Immunohistochemistry (IHC) was used to detect the expression of calcium-sensing receptor (CaSR) in 120 cases of lung adenocarcinoma with bone metastasis. Stably transfected cell lines with CaSR overexpression and knockdown based on A549 cells were constructed. The expression of CaSR was verified by western blot and qPCR. The proliferation and migration abilities of A549 cells were tested using cholecystokinin-8 (CCK-8) and Transwell assays, respectively. Western blotting was used to detect the expression of matrix metalloproteinases MMP2, MMP9, CaSR, and NF-?B. The supernatant from each cell culture group was collected as a conditional co-culture solution to study the induction of osteoclast precursor cells and osteoblasts. Western blot and qPCR were used to validate the expression of bone matrix degradation-related enzymes cathepsin K and hormone calcitonin receptor (CTR) and osteoblast-induced osteoclast maturation and differentiation enzyme receptor activator of nuclear factor-?B ligand (RANKL), macrophage colony-stimulating factor (M-CSF), osteoprotegerin (OPG), and PTHrP. Immunofluorescent staining was used to detect F-actin ring formation and osteocalcin expression. Western blot results for NF-?B expression identified a regulatory relationship between NF-?B and CaSR. Results: CaSR expression in lung cancer tissues was significantly higher than that in adjacent and normal lung tissues. The expression of CaSR in lung cancer tissues with bone metastasis was higher than that in non-metastatic lung cancer tissues. The proliferation and migration ability of A549 cells increased significantly with overexpressed CaSR. The co-culture solution directly induced osteoclast precursor cells and the expression of bone matrix degradation-related enzymes significantly increased. Osteoblasts were significantly inhibited and osteoblast-induced osteoclast maturation and differentiation enzymes were significantly downregulated. It was found that the expression of NF-?B and PTHrP increased when CaSR was overexpressed. Osteoclast differentiation factor expression was also significantly increased, which directly induces osteoclast differentiation and maturation. These results were reversed when CaSR was knocked down. Conclusions: CaSR can positively regulate NF-?B and PTHrP expression in A549 cells with a high metastatic potential, thereby promoting osteoclast differentiation and maturation, and facilitating the occurrence and development of bone metastasis in lung adenocarcinoma.

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Diethylnitrosamine induces lung adenocarcinoma in FVB/N mouse.

Publications

Diethylnitrosamine induces lung adenocarcinoma in FVB/N mouse.

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