Acidic extracellular pH promotes epithelial mesenchymal transition in Lewis lung carcinoma model

Cancer Cell International

Yasumasa Kato³  Kazuhiro Shimamura⁴  Yuh Baba¹  Toyonobu Maeda²  Atsuko Suzuki³ 

[1]Department of General Clinical Medicine, Ohu University School of Dentistry, Koriyama, Japan

[2]Department of Oral Function and Molecular Biology, Ohu University School of Dentistry, Koriyama, Japan

[3]Department of Oral Physiology and Biochemistry, Ohu University Graduate School of Dentistry, Koriyama, Japan

[4]Department of Oral Growth and Development, Ohu University School of Dentistry, Koriyama, Japan

关键词: MMP-9;    Lewis lung carcinoma;    EMT;    Invasion;    Acidic extracellular pH;   

Others  :  1121619
DOI  :  10.1186/s12935-014-0129-1

 received in 2014-08-04, accepted in 2014-11-13,  发布年份 2014

【 摘 要 】

Background

Epithelial mesenchymal transition (EMT) is thought to be an essential feature of malignant tumor cells when they spread into the stroma. Despite the extracellular acidity of tumor tissues, the effect of acidic extracellular pH (pH_e) on EMT in carcinoma models, including the Lewis lung carcinoma (LLC) model, remains unclear.

Methods

High and low metastatic LLC variants were generated by repeated tail vein injection of metastatic cells. DMEM/F12 medium, which has been supplemented with 15 mM HEPES, 4 mM phosphoric acid, and 1 g/L NaHCO₃ and adjusted to the desire pH with HCl or NaOH, was used for cell culture. EMT marker gene expression was determined by quantitative reverse transcription-polymerase chain reaction. Migration and invasion activities were analyzed by wound healing assay and the Boyden chamber assay through Matrigel®, respectively.

Results

Low metastatic variant LLCm1 cells showed a cobble-stone like morphology at pH_e 7.4. At pH_e 6.8, however, their morphology became fibroblastic, similar in shape to high metastatic variant LLCm4 cells. Steady state levels of matrix metalloproteinase-9 (Mmp9) mRNA were induced by acidic pH_e, maximizing at pH 6.8, with the levels of Mmp9 mRNA higher in LLCm4 than in LLCm1 cells. Both variants showed decreased levels of E-cadherin and increased levels of vimentin at pH_e 6.8. Acidic pH_e also induced expression of mRNAs encoding the E-cadherin repressors, Zeb2, Twist1 and Twist2, as well as enhancing cell motility and in vitro invasion through Matrigel®.

Conclusions

Acidic pH_e can induce EMT in some types of carcinoma.

【 授权许可】

   
2014 Suzuki et al.; licensee BioMed Central Ltd.

【 图 表 】

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