Evaluation of matrix metalloproteinase‐2 in lung cancer

Qin

International Journal of Molecular Medicine

et al. 2015

Abstract. Mammary serine protease inhibitor (maspin) is a tumor suppressor gene that is silenced in the majority of cancer cells during metastatic progression by transcriptional and epigenetic mechanisms. The function of maspin in non-small cell lung cancer cells (NSCLC) has not been clearly defined. In the present study, the expression of maspin in NSCLC cell lines, in particular, the adenocarcinoma cell lines, was heterogeneous. While the expression levels of maspin in PC-9 and H460 cell lines were intact, the expression of maspin in the A549 and SPC-A1 cells was hardly detected. Ectopic expression of maspin in A549 cells carrying the K-ras gene point mutation significantly inhibited cell migration and invasion abilities, which was associated with downregulated expression of matrix metalloproteinase-2 and integrin β1. Ectopic expression of maspin in SPC-A1 cells harboring the wild-type K-ras gene predominantly affected cell growth via targeting the AKT signaling molecules. Maspin functions differently in lung adenocarcinoma cells, possibly due to the varied molecular characteristics. IntroductionLung cancer is a leading cause of cancer mortality worldwide. Lung cancer is generally divided into non-small cell lung cancer cells (NSCLC) and SCLC, in which the NSCLC constitutes 80-85% of lung cancers. The three major NSCLC subtypes are adenocarcinoma, squamous cell carcinoma and large cell carcinoma. NSCLC, which is characterized by slow tumor cell growth and dissemination, is refractory to chemotherapy and chest radiotherapy. Several driven genes have been identified in NSCLC, such as EGFR, c-MET and the ALK-EML4 fusion gene (1). Treatment for lung cancer is mainly based on tumor stage, tumor pathology and molecular pathology. Understanding thoroughly the molecular mechanism underlying the aberrant cellular events driving lung cancer progressions is crucial for developing novel treatments.Mammary serine protease inhibitor (maspin), also known as Serpin B5, was first identified in 1994 (2). Maspin belongs to the serine protease inhibitor superfamily, and is predominantly localized in the cytoplasm, but is also localized in the nucleus and membrane, and is secreted. The exact roles of maspin in cancer are far more complicated than initially thought due to the conflicting experimental and clinical data that have been reported. In prostate cancer, the expression of maspin is frequently absent (3). Overexpression of maspin is considered an independent factor in predicting a favorable prognosis in breast cancer and lung squamous cell cancer (4-6). However, it has been also reported that the increased nuclear maspin expression predicts a favorable prognosis, whereas the enhanced cytoplasmic expression is associated with early-relapsing and unfavorable prognosis in breast cancer (7). Enhanced expression of maspin is correlated with unfavorable prognosis in pancreatic, ovarian and colorectal cancer (8-10). High maspin expression correlates with an unfavorable outcome in colorectal cancer in stage III and IV, suggesting th...

Section: Discussionsupporting

confidence: 44%

Different maspin functions in the lung adenocarcinoma A549 and SPC-A1 cell lines

Qin

International Journal of Molecular Medicine

et al. 2015

“…Elevated levels of SLPI protein have been observed in the bloodstream of patients with NSCLC [ 24 , 58 ]. While the matrix metalloproteinase MMP2 appears to play a role in lung cancer growth and migration [ 59 – 61 ], studies investigating levels of MMP2 in the bloodstream have reported inconsistent findings [ 62 – 64 ]. The diverse range of biological functions observed for markers identified in these studies are summarized in Table 4 .…”

Section: Discussionmentioning

confidence: 99%

Blood-based lung cancer biomarkers identified through proteomic discovery in cancer tissues, cell lines and conditioned medium

Birse¹,

Lagier²,

Fitzhugh³

et al. 2015

Clin Proteom

BackgroundSupport for early detection of lung cancer has emerged from the National Lung Screening Trial (NLST), in which low-dose computed tomography (LDCT) screening reduced lung cancer mortality by 20 % relative to chest x-ray. The US Preventive Services Task Force (USPSTF) recently recommended annual screening for the high-risk population, concluding that the benefits (life years gained) outweighed harms (false positive findings, abortive biopsy/surgery, radiation exposure). In making their recommendation, the USPSTF noted that the moderate net benefit of screening was dependent on the resolution of most false-positive results without invasive procedures. Circulating biomarkers may serve as a valuable adjunctive tool to imaging.ResultsWe developed a broad-based proteomics discovery program, integrating liquid chromatography/mass spectrometry (LC/MS) analyses of freshly resected lung tumor specimens (n = 13), lung cancer cell lines (n = 17), and conditioned media collected from tumor cell lines (n = 7). To enrich for biomarkers likely to be found at elevated levels in the peripheral circulation of lung cancer patients, proteins were prioritized based on predicted subcellular localization (secreted, cell-membrane associated) and differential expression in disease samples. 179 candidate biomarkers were identified. Several markers selected for further validation showed elevated levels in serum collected from subjects with stage I NSCLC (n = 94), relative to healthy smoker controls (n = 189). An 8-marker model was developed (TFPI, MDK, OPN, MMP2, TIMP1, CEA, CYFRA 21–1, SCC) which accurately distinguished subjects with lung cancer (n = 50) from high risk smokers (n = 50) in an independent validation study (AUC = 0.775).ConclusionsIntegrating biomarker discovery from multiple sample types (fresh tissue, cell lines and conditioned medium) has resulted in a diverse repertoire of candidate biomarkers. This unique collection of biomarkers may have clinical utility in lung cancer detection and diagnoses.Electronic supplementary materialThe online version of this article (doi:10.1186/s12014-015-9090-9) contains supplementary material, which is available to authorized users.

Journal of Controlled Release

“…Of the articles included in the database, methods utilized for upregulation quantification included: immunohistochemistry, qPCR, microarray analysis, Western blotting, ELISA, substrate zymography, and fluorogenic MMP substrates. Despite having discovered MMP upregulation in a variety of fluids (pleural effusion fluid[84], serum[85], plasma[86], ascitic fluid[87], sputum[88], pancreatic juices[89], urine[90], fecal material[91], bronchoalveolar lavage fluid[92], nipple aspirate fluids[93], and cerebrospinal fluid[94]), only literature evaluating normal and diseased human tissues was included in the database. Serum and plasma MMP concentrations were not included as upregulated cancer patient serum concentrations are often an order of magnitude lower than tissues obtained from healthy patients[85,95].…”

Section: Matrix Metalloproteinases In Cancer: Why Are They Worthwhilementioning

confidence: 99%

Matrix-metalloproteinases as targets for controlled delivery in cancer: An analysis of upregulation and expression

Isaacson

Jensen

Subrahmanyam

et al. 2017

116

While commonly known for degradation of the extracellular matrix, matrix metalloproteinases (MMPs) exhibit broad potential for use in targeting of bioactive and imaging agents in cancer treatment. MMPs are upregulated at all stages of expression in cancers. A comprehensive analysis of published literature on expression of all MMP subtypes at the genetic, protein, and activity levels in normal and diseased tissues indicate targeting applicability in a variety of cancers. This expression significantly increases at advanced cancer stages, providing an improved opportunity for controlled release in higher-stage patients. Since MMPs are integral at every stage of metastasis, MMP roles in cancer are discussed with a focus on MMP distribution and mobility within cells and tumors for cancer targeting applications. Several strategies for MMP utilization in targeting – such as matrix degradation, MMP cleavage, MMP binding, and MMP-induced environmental changes – are addressed.