Abstract
Thrombospondin 1 and thrombospondin 2 (THBS1 and THBS2) share similar multifunctional domains, and are known to be antiangiogenic. However, the expression pattern of THBS1 and THBS2 is different, and the specific role of THBS2 in different subtypes of lung cancer remains largely unclear. To evaluate the significance of THBS1 and THBS2 in the development of lung cancer, the present study performed a microarray-based systematic-analysis to determine the transcript levels of thrombospondins and their relation to the prognosis in lung cancer. THBS1 was in general underexpressed in lung cancer; in contrast, mRNA levels of THBS2 were markedly overexpressed in a number of datasets of non-small cell lung carcinoma (NSCLC), including lung adenocarcinoma (AC) and squamous cell carcinoma. Similar expression pattern of THBS1 and THBS2 was verified in pulmonary AC cell lines with real-time PCR analysis. The survival of lung AC patients with high THBS2 mRNA expression levels was poorer than patients with low levels of expression of THBS2. In a microarray-based analysis, genes coexpressed with THBS1 or THBS2 were determined. Pulmonary AC patients with a high expression level of sevenTSHB1-coexpressed genes (CCL5, CDH11, FYB, GZMK, LA-DQA1, PDE4DIP, and SELL) had better survival rates than those with a low expression level. Patients with a high expression of seven TSHB2-coexpressed genes (CHI3L1, COL5A2, COL11A1, FAP, MXRA5, THY1, and VCAN) had poor survival rates. Downregulation of VCAN and THBS2 with shRNA inhibited the cell proliferation in the A549 cell line. In summary, THBS1 functions as a tumor suppressor in lung adenocarcinoma. However, THBS2 may play a double-edged role in the progression of lung AC, i.e. anti-angiogenic and oncogenic function. Further study on the mechanism underlying the activity of THBS2 is warranted to have further implications for cancer diagnosis and treatment of pulmonary AC.
Highlights
Lung cancer is the leading cause of cancer mortality in the world in recent decades, accounting for about 20% of all cancer deaths in both men and women [1]
We focused on investigating the changes in THBS1 and THBS2 mRNA expression in lung cancer subtypes
Analysis of the expression levels of THBS1 in the two main subtypes of non-small cell lung cancer (NSCLC) in the same microarray dataset revealed decreased mRNA levels of THBS1 in both lung AD (Fig 1B and Table 1) and lung SCC (S3 Table), the data did not satisfy the threshold criteria set in this study
Summary
Lung cancer is the leading cause of cancer mortality in the world in recent decades, accounting for about 20% of all cancer deaths in both men and women [1]. There are two major types of lung cancer, non-small cell lung cancer (NSCLC) and small cell lung cancer, with 85% of cases due to NSCLC. NSCLC can be divided into three main subtypes: adenocarcinoma (AC, 40% of lung cancers), squamous cell carcinoma (SCC, 25–30% of lung cancers), and large cell carcinoma (10% of lung cancers). The 5-year survival rate for patients with NSCLC is less than 18%, and it is only about 7% for patients with small cell lung cancer [1]. Metastatic spread was reported in more than 70% of NSCLC patients with advanced-stage disease, with the metastases mainly affecting the brain, liver and bone sites. The patients died within 18 months or soon after. Investigating changes in the tumor-associated microenvironment during cancer progression is important for targeted therapy and improvement of clinical outcomes in lung cancer [2]
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