IL-6 regulates MMP-10 expression via JAK2/STAT3 signaling pathway in a human lung adenocarcinoma cell line.
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.
Zhang
Xiaoying
X
The Third Affiliated Hospital of Suzhou University, Jiangsu Changzhou 213003, People's Republic of China. Xiaoyingzhang6689996@msn.com
Yin
Peiji
P
DI
Dongmei
D
Luo
Guanghua
G
Zheng
Lu
L
Wei
Jiang
J
Zhang
Jun
J
Shi
Yuanping
Y
Zhang
Jichen
J
Xu
Ning
N
D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D053506:Matrix Metalloproteinase 10 / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020032:Tyrphostins / Q000494:pharmacology
D015850:Interleukin-6; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D053506:Matrix Metalloproteinase 10