High-mobility group box 1-mediated matrix metalloproteinase-9 expression in non-small cell lung cancer contributes to tumor cell invasiveness.
High-mobility group box 1 (HMGB1) is a versatile protein with intranuclear and extracellular functions. It is involved in invasion and metastasis in various human malignancies. However, the role of HMGB1 in non-small cell lung cancer (NSCLC) is unclear. We hypothesized that HMGB1 expression is a determinant of cellular invasiveness and metastasis in lung cancer. We examined HMGB1 expression in 48 NSCLC specimens by quantitative real-time PCR. High HMGB1 expression was significantly associated with clinically advanced stages (stage III-IV) (P < 0.05) and was correlated to expression of matrix metalloproteinase-9 (MMP-9) (P < 0.05). Patients with high levels of HMGB1 expression had poorer clinical prognosis. The expression level of MMP-9 and metastatic ability in vitro were significantly higher in an HMGB1-overexpressing human NSCLC cell lines (A549 and H23). The treatment with HMGB1 small interfering RNA reduced MMP-9 expression and the cellular metastatic ability in NSCLC cells. We also demonstrated that phosphoinositide 3-kinase/Akt and NF-κB-related pathways contributed to the HMGB1-induced MMP-9 expression and cellular metastatic ability.
Liu
Po-Len
PL
Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
Tsai
Jong-Rung
JR
Hwang
Jhi-Jhu
JJ
Chou
Shah-Hwa
SH
Cheng
Yu-Jen
YJ
Lin
Feng-Yen
FY
Chen
Yuh-Lien
YL
Hung
Chun-Ying
CY
Chen
Wen-Chi
WC
Chen
Yung-Hsiang
YH
Chong
Inn-Wen
IW
D000328:Adult; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D024243:HMGB1 Protein; D016328:NF-kappa B; D012333:RNA, Messenger; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9