Abstract
Small cell lung cancer (SCLC) is highly aggressive and is characterized by malignant metastasis. Approximately 90% of patients die due to extensive metastasis. The extracellular matrix (ECM) is a natural barrier that can prevent cellular invasion and metastasis. Therefore, degradation of the ECM must take place in order for extensive metastasis to occur. A disintegrin and metalloprotease (ADAM) is a multi-domain protease that plays an important role in tumorigenesis, as well as tumor development, invasion and metastasis. However, there have been few reports on the expression and role of ADAMs in SCLC. In the current study, the expression and role of ADAMs in SCLC proliferation, invasion and metastasis was investigated. A total of 150 SCLC tissue samples were examined by immunohistochemistry for ADAMs expression. ADAM-12 was found to be abundantly expressed in 72.67% samples and other ADAMs were found to be expressed in 10% to 40% of samples. ADAM-12 levels in serum and urine, from 70 SCLC patients and 40 normal controls, were also measured using ELISA. ADAM-12 expression was significantly higher in SCLC patients than in healthy controls and in patients with extensive disease compared to those with more limited disease. Silencing the expression of ADAM-12 in H1688 cells through the use of specific siRNA significantly reduced cellular proliferation, invasion and metastasis. Supplementing the expression of ADAM-12-L or -S in H345 cells, significantly enhanced cellular proliferation, invasion and metastasis. Animal models with metastatic SCLC also exhibited increased expression of ADAM-12 along with enhanced invasion and metastasis. In brief, ADAM-12 is an independent prognostic factor and diagnostic marker, and is involved in the proliferation, invasion and metastasis of SCLC.
Highlights
Small cell lung cancer (SCLC) is the most malignant of all lung cancers
The positive expression of A disintegrin and metalloprotease (ADAM)-12 was the highest at 72.67% (109/150) and the strong positive expression of ADAM12 was significantly greater compared with the other ADAMs (P, 0.001)
ADAM-12 was expressed significantly more in SCLC tissue samples compared with the expression of other ADAMs (P,0.001) indicating that ADAM-12 may play an important role in the process of proliferation, invasion and metastasis in SCLC
Summary
Small cell lung cancer (SCLC) is the most malignant of all lung cancers. The five-year survival rate is only 3–8% due to the widespread metastasis during the early stage and relapses that occur when resistance to the treatments develops [1]. The degradation of the extracellular matrix (ECM) has been the main focus of studies on the invasion and metastasis of SCLC [2,3]. Inhibitors of MMPs have been used clinically for SCLC patients, but proved to be ineffective and did not improve the five-year survival rate of the patients [5]. This suggests that the degradation of ECM is a complex process and that proteases, other than MMPs, should be studied to determine whether other factors play a role in SCLC
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