IL-6 regulates MMP-10 expression via JAK2/STAT3 signaling pathway in a human lung adenocarcinoma cell line.

Abstract

We previously reported that matrix metalloproteinase (MMP)-10 mRNA levels were significantly lower in tumor tissues than in adjacent normal tissues in human non-small cell lung cancer (NSCLC), whereas protein levels of MMP-10 were higher in the tumor tissues than the adjacent tissues. The mechanism of this divergence is still unknown. In the present study the role of Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) on interleukin (IL)-6 mediated regulation of MMP-10 expression was investigated in a human lung adenocarcinoma cell line (A549 cells) and the molecular regulatory mechanism of MMP-10 expression was explored. A549 cells were stimulated by different concentrations of IL-6 with or without AG490, a specific JAK2 inhibitor. It was demonstrated that IL-6 moderately reduced the MMP-10 mRNA levels, whereas it significantly enhanced the MMP-10 protein mass in the A549 cells. This phenomenon mimicked the divergence of mRNA level and protein mass of MMP-10 in human NSCLC. Moreover, the present study indicated that IL-6 regulation of MMP-10 expression was via the JAK2/STAT3 pathway. STAT3 mRNA levels were significantly increased when the cells were treated with IL-6, whereas when AG490 (50 muM) was added to the cell cultures, IL-6-induced increase of STAT3 mRNA levels was abolished. Meanwhile, AG490 blocked the IL-6-induced inhibition of MMP-10 mRNA as well as blocking the IL-6-induced increase of MMP-10 protein mass in the A549 cells. Neither IL-6 nor AG490 influenced JAK2 mRNA levels in the A549 cell cultures. It is concluded that the JAK2/STAT3 pathway is involved in the IL-6-mediated regulation of MMP-10, and IL-6 can moderately reduce MMP-10 mRNA levels and strongly increase MMP-10 protein mass in human lung adenocarcinoma A549 cells. Contrasting effects of IL-6 on MMP-10 mRNA level and protein concentration in A549 cells may partially explain the divergence of MMP-10 mRNA level and protein mass in human NSCLC.

• Authors: Xiaoying Zhang, Peiji Yin, Dongmei DI, Guanghua Luo, Lu Zheng, Jiang Wei, Jun Zhang, Yuanping Shi, Jichen Zhang, Ning Xu
• Journal: Anticancer research (Anticancer Res) Vol. 29 Issue 11 Pg. 4497-501 (Nov 2009) ISSN: 1791-7530 [Electronic] Greece
• PMID: 20032397 (Publication Type: Journal Article)

Chemical References

• Interleukin-6
• RNA, Messenger
• STAT3 Transcription Factor
• STAT3 protein, human
• Tyrphostins
• alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
• JAK2 protein, human
• Janus Kinase 2
• Matrix Metalloproteinase 10

Topics

• Adenocarcinoma (enzymology, genetics, metabolism)
• Cell Line, Tumor
• Gene Expression Regulation, Enzymologic (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Interleukin-6 (pharmacology)
• Janus Kinase 2 (antagonists & inhibitors, metabolism)
• Lung Neoplasms (enzymology, genetics, metabolism)
• Matrix Metalloproteinase 10 (biosynthesis, genetics)
• RNA, Messenger (biosynthesis, genetics)
• STAT3 Transcription Factor (biosynthesis, genetics, metabolism)
• Signal Transduction
• Tyrphostins (pharmacology)